Azido nucleosides and nucleotide analogs

ABSTRACT

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof. Examples of viral infections include a respiratory syncytial viral (RSV) and influenza infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/531,552, filed Nov. 3, 2014, now U.S. Pat. No. 9,346,848, entitled“AZIDO NUCLEOSIDES AND NUCLEOTIDES ANALOGS” which is a continuation ofU.S. application Ser. No. 13/236,486, filed Sep. 19, 2011, now U.S. Pat.No. 8,877,731, entitled “AZIDO NUCLEOSIDES AND NUCLEOTIDES ANALOGS”which claims priority to U.S. Provisional Patent Application No.61/385,441, entitled “AZIDO NUCLEOSIDES AND NUCLEOTIDES ANALOGS” filedSep. 22, 2010; which are all incorporated herein by reference in theirentireties, including any drawings.

BACKGROUND

1. Field

The present application relates to the fields of chemistry, biochemistryand medicine. More particularly, disclosed herein are nucleoside,nucleotides and analogs thereof, pharmaceutical compositions thatinclude one or more nucleosides, nucleotides and analogs thereof, andmethods of synthesizing the same. Also disclosed herein are methods ofameliorating and/or treating a paramyxovirus and/or an orthomyxovirusviral infection with one or more nucleosides, nucleotides and analogsthereof.

2. Description

Respiratory viral infections, including upper and lower respiratorytract viral infections, infects and is the leading cause of death ofmillions of people each year. Upper respiratory tract viral infectionsinvolve the nose, sinuses, pharynx and/or larynx. Lower respiratorytract viral infections involve the respiratory system below the vocalcords, including the trachea, primary bronchi and lungs.

Nucleoside analogs are a class of compounds that have been shown toexert antiviral activity both in vitro and in vivo, and thus, have beenthe subject of widespread research for the treatment of viralinfections. Nucleoside analogs are usually therapeutically inactivecompounds that are converted by host or viral enzymes to theirrespective active anti-metabolites, which, in turn, may inhibitpolymerases involved in viral or cell proliferation. The activationoccurs by a variety of mechanisms, such as the addition of one or morephosphate groups and, or in combination with, other metabolic processes.

SUMMARY

Some embodiments disclosed herein relate to a compound of Formula (I) ora pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to methods of amelioratingand/or treating a paramyxovirus viral infection that can includeadministering to a subject suffering from the paramyxovirus viralinfection a therapeutically effective amount of one or more compounds ofFormula (I) and/or Formula (II), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition that includes one or morecompounds of Formula (I) and/or Formula (II), or a pharmaceuticallyacceptable salt thereof. Other embodiments described herein relate tousing one or more compounds of Formula (I) and/or Formula (II), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for ameliorating and/or treating a paramyxovirus viralinfection. Still other embodiments described herein relate to compoundsof Formula (I) and/or Formula (II), or a pharmaceutically acceptablesalt thereof, that can be used for ameliorating and/or treating aparamyxovirus viral infection. Yet still other embodiments disclosedherein relate to methods of ameliorating and/or treating a paramyxovirusviral infection that can include contacting a cell infected with theparamyxovirus viral infection with a therapeutically effective amount ofone or more compounds of Formula (I) and/or Formula (II), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I) and/orFormula (II), or a pharmaceutically acceptable salt thereof. Someembodiments disclosed herein relate to methods of inhibiting thereplication of a paramyxovirus that can include contacting a cellinfection with the paramyxovirus with an effective amount of one or morecompounds of Formula (I) and/or Formula (II), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includesone or more compounds of Formula (I) and/or Formula (II), or apharmaceutically acceptable salt thereof. For example, the paramyxovirusviral infection can be a respiratory syncytial viral infection.

Some embodiments disclosed herein relate to methods of amelioratingand/or treating an orthomyxovirus viral infection that can includeadministering to a subject suffering from the orthomyxovirus viralinfection a therapeutically effective amount of one or more compounds ofFormula (I) and/or Formula (II), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition that includes one or morecompounds of Formula (I) and/or Formula (II), or a pharmaceuticallyacceptable salt thereof. Other embodiments described herein relate tousing one or more compounds of Formula (I) and/or Formula (II), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for ameliorating and/or treating an orthomyxovirus viralinfection. Still other embodiments described herein relate to compoundsof Formula (I) and/or Formula (II), or a pharmaceutically acceptablesalt thereof, that can be used for ameliorating and/or treating anorthomyxovirus viral infection. Yet still other embodiments disclosedherein relate to methods of ameliorating and/or treating anorthomyxovirus viral infection that can include contacting a cellinfected with the orthomyxovirus viral infection with a therapeuticallyeffective amount of one or more compounds of Formula (I) and/or Formula(II), or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I) and/orFormula (II), or a pharmaceutically acceptable salt thereof. Someembodiments disclosed herein relate to methods of inhibiting thereplication of an orthomyxovirus that can include contacting a cellinfection with the orthomyxovirus with an effective amount of one ormore compounds of Formula (I) and/or Formula (II), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includesone or more compounds of Formula (I) and/or Formula (II), or apharmaceutically acceptable salt thereof. For example, theorthomyxovirus viral infection can be an influenza viral infection (suchas influenza A, B and/or C).

Some embodiments disclosed herein relate to methods of amelioratingand/or treating a paramyxovirus viral infection and/or an orthomyxovirusviral infection that can include administering to a subject sufferingfrom the viral infection a therapeutically effective amount of acompound described herein or a pharmaceutically acceptable salt thereof(for example, one or more compounds of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes one or more compounds described herein, incombination with one or more agents described herein. Some embodimentsdisclosed herein relate to methods of ameliorating and/or treating aparamyxovirus viral infection and/or an orthomyxovirus viral infectionthat can include contacting a cell infected with the viral infectionwith a therapeutically effective amount of a compound described hereinor a pharmaceutically acceptable salt thereof (for example, one or morecompounds of Formula (I), or a pharmaceutically acceptable saltthereof), or a pharmaceutical composition that includes one or morecompounds described herein, in combination with one or more agentsdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows example RSV agents.

DETAILED DESCRIPTION

Human Respiratory Syncytial Virus (RSV) is a member of theParayxoviridae family. RSV is a single stranded RNA virus. RSV can causerespiratory infections, and can be associated with bronchiolitis andpneumonia.

RSV is transmitted person to person via direct or close contact withcontaminated respiratory droplets or fomites. Symptoms of an RSVinfection include coughing, sneezing, runny nose, fever, decrease inappetite, and wheezing. RSV is the most common cause of bronchiolitisand pneumonia in children under one year of age in the world, and can bethe cause of tracheobronchitis in older children and adults. In theUnited States, between 75,000 and 125,000 infants are hospitalized eachyear with RSV. Among adults older than 65 years of age, an estimated14,000 deaths and 177,000 hospitalizations have been attributed to RSV.

Treatment options for people infected with RSV are currently limited.Antibiotics, usually prescribed to treat bacterial infections, andover-the-counter medication are not effective in treating RSV and mayhelp only to relieve some of the symptoms. In severe cases, a nebulizedbronchodilator, such as albuterol, may be prescribed to relieve some ofthe symptoms, such as wheezing. RespiGram® (RSV-IGIV, MedImmune,approved for high risk children younger than 24 months of age), Synagis®(palivizumab, MedImmune, approved for high risk children younger than 24months of age), and Virzole® (ribavirin by aerosol, ICN pharmaceuticals)have been approved for treatment of RSV.

Influenza is a single stranded RNA virus and a member of theOrthomyxoviridae family. There are currently three species of influenza;influenza A, influenza B and influenza C. Influenza A has been furtherclassified based on the viral surface proteins into hemagglutinin (H orHA) and neuramididase (N). There are approximately 16H antigens (H1 toH16) and 9 N antigens (N1 to N9). Influenza A includes several subtype,including H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8,H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H1ON7. As with RSV, influenzaviruses can be transmitted from person to person via direct contact withinfected secretions and/or contaminated surfaces or objections.Complications from an influenza viral infection include pneumonia,bronchitis, dehydration, and sinus and ear infections. Medicationscurrently approved by the FDA against an influenza infection includeamantadine, rimantadine, Relenza® (zanamivir, GlaxoSmithKline) andTamiflu® (oseltamivir, Genentech).

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R*, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹,R^(1a), R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a), R^(9a),R^(10a), R^(11a), R^(12a), R^(13a), R^(14a), R^(15a), R^(16a), R^(17a),R^(18a), R^(19a), R^(20a), R^(21a), R^(22a), R^(23a), R^(24a), R^(25a),R^(26a), R^(27a), R^(28a), R^(29a), R^(30a), R^(31a), R^(a), R^(b),R^(A), R^(B) and R^(C) represent substituents that can be attached tothe indicated atom. An R group may be substituted or unsubstituted. Iftwo “R” groups are described as being “taken together” the R groups andthe atoms they are attached to can form a cycloalkyl, aryl, heteroarylor heterocycle. For example, without limitation, if R^(1a) and R^(1b) ofan NR^(1a)R^(1b) group are indicated to be “taken together,” it meansthat they are covalently bonded to one another to form a ring:

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more of the indicated substituents. If nosubstituents are indicated, it is meant that the indicated “optionallysubstituted” or “substituted” group may be substituted with one or moregroup(s) individually and independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl,hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio,arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, an amino, a mono-substituted amino group anda di-substituted amino group, and protected derivatives thereof.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, thealkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of thecycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of theheteroaryl or ring of the heteroalicyclyl can contain from “a” to “b”,inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” grouprefers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—,CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and(CH₃)₃C—. If no “a” and “b” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl,heteroaryl or heteroalicyclyl group, the broadest range described inthese definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. When composed of two or more rings, the rings may be joinedtogether in a fused fashion. A cycloalkynyl group may be unsubstitutedor substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen andsulfur. The number of atoms in the ring(s) of a heteroaryl group canvary. For example, the heteroaryl group can contain 4 to 14 atoms in thering(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).Furthermore, the term “heteroaryl” includes fused ring systems where tworings, such as at least one aryl ring and at least one heteroaryl ring,or at least two heteroaryl rings, share at least one chemical bond.Examples of heteroaryl rings include, but are not limited to, furan,furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole,benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine,pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,and triazine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfur,and nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heteroalicyclic may be quaternized.Heterocyclyl or heteroalicyclic groups may be unsubstituted orsubstituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groupsinclude but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane,1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline, 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aralkyl may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and theirbenzo-fused analogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl)methyl,(piperidin-4-yl)ethyl, (piperidin-4-yl)propyl,(tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3-thiazinan-4-yl)methyl.

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or acycloalkynyl is defined as above. A non-limiting list of alkoxys aremethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy and tert-butoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may besubstituted or unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl, such as but not limited to phenyl. Both an aryloxy andarylthio may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. Asulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or(heteroalicyclyl)alkyl, as defined herein. An O-carboxy may besubstituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein Xis a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein X is a halogen and R_(A) hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An S-sulfonamidomay be substituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-sulfonamidomay be substituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-carbamyl maybe substituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-carbamyl maybe substituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-thiocarbamylmay be substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-thiocarbamylmay be substituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. A C-amido may besubstituted or unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-amido may besubstituted or unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The term “nucleoside” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a compound composed of anoptionally substituted pentose moiety or modified pentose moietyattached to a heterocyclic base or tautomer thereof via a N-glycosidicbond, such as attached via the 9-position of a purine-base or the1-position of a pyrimidine-base. Examples include, but are not limitedto, a ribonucleoside comprising a ribose moiety and adeoxyribonucleoside comprising a deoxyribose moiety. A modified pentosemoiety is a pentose moiety in which an oxygen atom has been replacedwith a carbon and/or a carbon has been replaced with a sulfur or anoxygen atom. A “nucleoside” is a monomer that can have a substitutedbase and/or sugar moiety. Additionally, a nucleoside can be incorporatedinto larger DNA and/or RNA polymers and oligomers. In some instances,the nucleoside can be a nucleoside analog drug.

The term “nucleotide” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a nucleoside having aphosphate ester bound to the pentose moiety, for example, at the5′-position.

As used herein, the term “heterocyclic base” refers to an optionallysubstituted nitrogen-containing heterocyclyl that can be attached to anoptionally substituted pentose moiety or modified pentose moiety. Insome embodiments, the heterocyclic base can be selected from anoptionally substituted purine-base, an optionally substitutedpyrimidine-base and an optionally substituted triazole-base (forexample, a 1,2,4-triazole). The term “purine-base” is used herein in itsordinary sense as understood by those skilled in the art, and includesits tautomers. Similarly, the term “pyrimidine-base” is used herein inits ordinary sense as understood by those skilled in the art, andincludes its tautomers. A non-limiting list of optionally substitutedpurine-bases includes purine, adenine, guanine, hypoxanthine, xanthine,alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine,caffeine, uric acid and isoguanine. Examples of pyrimidine-basesinclude, but are not limited to, cytosine, thymine, uracil,5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). Anexample of an optionally substituted triazole-base is1,2,4-triazole-3-carboxamide. Other non-limiting examples ofheterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (e.g.,8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine,7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine,5-halouracil (e.g., 5-fluorouracil and 5-bromouracil),pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic basesdescribed in U.S. Pat. Nos. 5,432,272 and 7,125,855, which areincorporated herein by reference for the limited purpose of disclosingadditional heterocyclic bases. In some embodiments, a heterocyclic basecan be optionally substituted with an amine or an enol protectinggroup(s).

The term “—N-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via a main-chain amino or mono-substituted aminogroup. When the amino acid is attached in an —N-linked amino acid, oneof the hydrogens that is part of the main-chain amino ormono-substituted amino group is not present and the amino acid isattached via the nitrogen. As used herein, the term “amino acid” refersto any amino acid (both standard and non-standard amino acids),including, but not limited to, α-amino acids, β-amino acids, γ-aminoacids and δ-amino acids. Examples of suitable amino acids include, butare not limited to, alanine, asparagine, aspartate, cysteine, glutamate,glutamine, glycine, proline, serine, tyrosine, arginine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, threonine,tryptophan and valine. Additional examples of suitable amino acidsinclude, but are not limited to, ornithine, hypusine, 2-aminoisobutyricacid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine,alpha-ethyl-glycine, alpha-propyl-glycine and norleucine. N-linked aminoacids can be substituted or unsubstituted.

The term “—N-linked amino acid ester derivative” refers to an amino acidin which a main-chain carboxylic acid group has been converted to anester group. In some embodiments, the ester group has a formula selectedfrom alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— andaryl(alkyl)-O—C(═O)—. A non-limiting list of ester groups include,methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—,n-butyl-O—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—,neopentyl-O—C(═O)—, cyclopropyl-O—C(═O)—, cyclobutyl-O—C(═O)—,cyclopentyl-O—C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—, andbenzyl-O—C(═O)—. N-linked amino acid ester derivatives can besubstituted or unsubstituted.

The terms “phosphorothioate” and “phosphothioate” refer to a compound ofthe general formula

its protonated forms (for example,

and its tautomers (such as

As used herein, the term “phosphate” is used in its ordinary sense asunderstood by those skilled in the art, and includes its protonatedforms (for example,

As used herein, the terms “monophosphate,” “diphosphate,” and“triphosphate” are used in their ordinary sense as understood by thoseskilled in the art, and include protonated forms.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes, and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ preferred, ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. In addition, the term“comprising” is to be interpreted synonymously with the phrases “havingat least” or “including at least”. When used in the context of aprocess, the term “comprising” means that the process includes at leastthe recited steps, but may include additional steps. When used in thecontext of a compound, composition or device, the term “comprising”means that the compound, composition or device includes at least therecited features or components, but may also include additional featuresor components. Likewise, a group of items linked with the conjunction‘and’ should not be read as requiring that each and every one of thoseitems be present in the grouping, but rather should be read as ‘and/or’unless expressly stated otherwise. Similarly, a group of items linkedwith the conjunction ‘or’ should not be read as requiring mutualexclusivity among that group, but rather should be read as ‘and/or’unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included. For example alltautomers of a phosphate and a phosphorothioate groups are intended tobe included. Examples of tautomers of a phosphorothioate include thefollowing:

Furthermore, all tautomers of heterocyclic bases known in the art areintended to be included, including tautomers of natural and non-naturalpurine-bases and pyrimidine-bases.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein:

wherein B¹ can be selected from an optionally substituted heterocyclicbase and an optionally substituted heterocyclic base with a protectedamino group; R¹ can be selected from hydrogen, an optionally substitutedacyl,

n can be 0, 1 or 2; R² and R³ can be independently selected fromhydrogen, an optionally substituted C₁₋₆ alkyl and an optionallysubstituted C₁₋₆ haloalkyl; R⁴ can be selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, —OR¹⁸ and —OC(═O)R¹⁹; R⁵ can beselected from hydrogen, halogen, optionally substituted C₁₋₆ alkyl,—OR²⁰ and —OC(═O)R²¹, or when R¹ is

and R¹⁴ is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl, thenR¹⁵ and R⁵ together can be O, or when R¹ is

and R¹⁶ is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl, thenR¹⁷ and R⁵ together can be O; R⁶ can be selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, —OR²² and —OC(═O)R²³; or R⁵ and R⁶can be both oxygen atoms and linked together by a carbonyl group; R⁷ canbe selected from hydrogen, halogen, optionally substituted C₁₋₆ alkyl,—OR²⁴ and —OC(═O)R²⁵; R⁸ can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl and an optionally substituted C₁₋₆ haloalkyl; R⁹,R¹⁰, each R¹¹, R¹² and R¹³ can be independently absent or hydrogen; R¹⁴can be selected from an —O— optionally substituted aryl, an —O—optionally substituted heteroaryl and an —O— optionally substitutedheterocyclyl, and R¹⁵ can be

or R¹⁴ can be an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative, and R¹⁵ canbe an optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative; or R¹⁴ can be O⁻,hydroxy or an —O— optionally substituted C₁₋₆ alkyl, and R¹⁵ and R⁵together can be O; R¹⁶ can be selected from the group consisting of an—O— optionally substituted aryl, an —O— optionally substitutedheteroaryl and an —O— optionally substituted heterocyclyl, and R¹⁷ canbe an optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative; or R¹⁶ can be anoptionally substituted N-linked amino acid or an optionally substitutedN-linked amino acid ester derivative, and R¹⁷ can be an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative; or R¹⁶ can be O⁻, hydroxy or an —O—optionally substituted C₁₋₆ alkyl, and R¹⁷ and R⁵ together can be O;R¹⁸, R²⁰, R²² and R²⁴ can be independently selected from hydrogen and anoptionally substituted C₁₋₆ alkyl; R¹⁹, R²¹, R²³ and R²⁵ can beindependently selected from an optionally substituted C₁₋₆ alkyl and anoptionally substituted C₃₋₆ cycloalkyl; R²⁶ can be hydrogen or anoptionally substituted C₁₋₄-alkyl; R²⁷ can be selected from hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl, and anoptionally substituted aryl(C₁₋₆ alkyl); and R²⁸ can be selected fromhydrogen, an optionally substituted C₁₋₆-alkyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₆ alkyl), and an optionally substitutedhaloalkyl, or R²⁶ and R²⁷ can be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl.

R¹ can be various substituents. In some embodiments, R¹ can be hydrogenwhen at least one of R² and R³ is an optionally substituted C₁₋₆ alkylor an optionally substituted C₁₋₆ haloalkyl. In some embodiments, R¹,R², R³, R⁴, and R⁸ are all hydrogen, and B¹ is an optionally substituted

as described herein.

In some embodiments, R¹ can be an acyl. For example, R¹ can be —C(═O)H,—C(═O)— an optionally substituted alkyl, —C(═O)— an optionallysubstituted alkenyl, —C(═O)— an optionally substituted alkynyl, or—C(═O)— an optionally substituted aryl. In some embodiments, —C(═O)— anoptionally substituted alkyl can be an —C(═O)— an optionally substitutedC₁₋₆ alkyl. In other embodiments, —C(═O)— an optionally substitutedalkenyl can be an —C(═O)— an optionally substituted C₂₋₆ alkenyl. Instill other embodiments, —C(═O)— an optionally substituted alkynyl canbe an —C(═O)— an optionally substituted C₂₋₆ alkynyl. In yet still otherembodiments, —C(═O)— an optionally substituted aryl can be an —C(═O)— anoptionally substituted C₆₋₁₀ aryl.

In some embodiments, R¹ can be

wherein n can be 0, 1 or 2. Those skilled in the art understand thatwhen n is 0, R¹ can be a mono-phosphate. Likewise, when n is 1 or 2,those skilled in the art understand R¹ can be a di-phosphate or atri-phosphate, respectively. In some embodiments, at least one of R⁹,R¹⁰ and R¹¹ can be absent. Those skilled in the art understand that whenR⁹, R¹⁰ and/or R¹¹ is absent, the oxygen associated with R⁹, R¹⁰ and/orR¹¹ can have a negative charge, which can be denoted as O⁻. In someembodiments, at least one of R⁹, R¹⁰ and R¹¹ can be hydrogen. In someembodiments, n can be 0, and R⁹ and R¹⁰ can be both absent. In otherembodiments, n can be 0, and R⁹ and R¹⁰ can be both hydrogen. In someembodiments, n can be 1, and R⁹, R¹⁰ and R¹¹ can be absent. In otherembodiments, n can be 1, and R⁹, R¹⁰ and R¹¹ can be hydrogen. In someembodiments, n can be 2, and R⁹, R¹⁰ and each R¹¹ can be absent. Inother embodiments, n can be 2, and R⁹, R¹⁰ and each R¹¹ can be hydrogen.In some embodiments, R¹ can be

when B¹ is selected from a substituted adenine, substituted guanine,substituted 5-methyuracil, substituted uracil and

wherein R* can be selected from an acyl, —O-amide, an optionallysubstituted C₁₋₆ alkyl and an optionally substituted C₃₋₇ cycloalkyl;and Y can be selected from any of the substituents included in thedefinition of “substituted;” and m can be an integer in the range of 1to 2. In some embodiments, R¹ can be

when B¹ is a substituted adenine or substituted guanine.

In some embodiments, R¹ can be

In some embodiments, at least one of R¹² and R¹³ can be absent. Forexample, R¹² can be absent, R¹³ can be absent or R¹² and R¹³ can beabsent. Those skilled in the art understand that when R¹² and/or R¹³ areabsent, the oxygen associated with R¹² and/or R¹³ can have a negativecharge, respectively, which can be denoted as O⁻. In some embodiments,at least one of R¹² and R¹³ can be hydrogen. Examples of at least one ofR¹² and R¹³ being hydrogen include the following:

In some embodiments, both R¹² and R¹³ can be hydrogen.

In some embodiments, R¹ can be

In some embodiment, R¹⁴ can be selected from an —O— optionallysubstituted aryl, an —O— optionally substituted heteroaryl and an —O—optionally substituted heterocyclyl, and R¹⁵ can be

In some embodiments, R¹⁴ can be an —O— optionally substitutedheteroaryl. In other embodiments, R¹⁴ can be an —O— optionallysubstituted heterocyclyl. In some embodiments, R¹⁴ can be an —O—optionally substituted aryl. For example, the —O—optionally substitutedaryl can be an —O— optionally substituted phenyl or an —O— optionallysubstituted naphthyl. If R¹⁴ is an —O-substituted phenyl, the phenylring can be substituted one or more times. Likewise, if R¹⁴ is an—O-substituted naphthyl, the naphthyl ring can be substituted one ormore times. Suitable substituents that can be present on an —O—optionally substituted phenyl and an —O— optionally substituted naphthylinclude electron-donating groups and electron-withdrawing groups. Insome embodiments, R¹⁴ can be an —O-para-substituted phenyl. In otherembodiment, R¹⁴ can be an —O-unsubstituted phenyl or an —O-unsubstitutednaphthyl.

In some embodiments, when R¹⁵ has the structure

then R²⁶ can be selected from hydrogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, anoptionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆alkyl); R²⁷ can be hydrogen or an optionally substituted C₁₋₄-alkyl; andR²⁸ can be selected from hydrogen, an optionally substituted C₁₋₆-alkyl,an optionally substituted C₃₋₆ cycloalkyl, an optionally substitutedaryl, an optionally substituted aryl(C₁₋₆ alkyl) and an optionallysubstituted C₁₋₆ haloalkyl, or R²⁶ and R²⁷ can be taken together to forman optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, R²⁶ can be hydrogen. In other embodiments, R²⁶ canbe an optionally substituted C₁₋₆-alkyl. Examples of suitable optionallysubstituted C₁₋₆-alkyls include optionally substituted variants of thefollowing: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl (branched and straight-chained), and hexyl (branchedand straight-chained). When R²⁶ is substituted, R²⁶ can be substitutedwith one or more substituents selected from N-amido, mercapto,alkylthio, an optionally substituted aryl, hydroxy, an optionallysubstituted heteroaryl, O-carboxy, and amino. In some embodiment, R²⁶can be an unsubstituted C₁₋₆-alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In anembodiment, R²⁶ can be methyl.

In some embodiments, R²⁷ can be hydrogen. In other embodiments, R²⁷ canbe an optionally substituted C₁₋₄-alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment,R²⁷ can be methyl. In some embodiments, R²⁶ and R²⁷ can be takentogether to form an optionally substituted C₃₋₆ cycloalkyl. Depending onthe groups that are selected for R²⁶ and R²⁷, the carbon to which R²⁶and R²⁷ are attached may be a chiral center. In some embodiment, thecarbon to which R²⁶ and R²⁷ are attached may be a (R)-chiral center. Inother embodiments, the carbon to which R²⁶ and R²⁷ are attached may be a(S)-chiral center.

As to R²⁸, in some embodiments, R²⁸ can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments, R²⁸ can be an optionally substituted C₃₋₆ cycloalkyl. Forexample, R²⁸ can be an optionally substituted cyclopropyl, an optionallysubstituted cyclobutyl, an optionally substituted cyclopentyl or anoptionally substituted cyclohexyl. In some embodiments, R²⁸ can be anoptionally substituted cyclohexyl. In still other embodiments, R²⁸ canbe an optionally substituted aryl, such as optionally substituted phenyland optionally substituted naphthyl. In yet still other embodiments, R²⁸can be an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments,R²⁸ can be an optionally substituted benzyl. In some embodiments, R²⁸can be an optionally substituted C₁₋₆ haloalkyl, for example, CF₃. Insome embodiments, R²⁸ can be hydrogen.

In some embodiments, R¹⁴ can be an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivative,and R¹⁵ can be an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative. Variousamino acids and amino acid ester derivatives can be used, includingthose described herein. In some embodiments, one or both of R¹⁴ and R¹⁵can be an optionally substituted N-linked α-amino acid. Suitable aminoacids include, but are not limited to, alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. In other embodiments,one or both of R¹⁴ and R¹⁵ can be an optionally substituted N-linkedα-amino acid ester derivative. For example, R¹⁴ and/or R¹⁵ can be anester derivative of any of the following an amino acids describedherein: alanine, asparagine, aspartate, cysteine, glutamate, glutamine,glycine, proline, serine, tyrosine, arginine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, threonine, tryptophan andvaline. In some embodiment, one or both of R¹⁴ and R¹⁵ can be an esterderivative of alanine. In some embodiments, one or both of R¹⁴ and R¹⁵can be an optionally substituted N-linked amino acid C₁₋₆ alkyl ester.In some embodiments, one or both of R¹⁴ and R¹⁵ can be an optionallysubstituted N-linked amino acid C₃₋₆ cycloalkyl ester. In someembodiments, the optionally substituted N-linked amino acid or theoptionally substituted N-linked amino acid ester derivative can be inthe L-configuration. In other embodiments, the optionally substitutedN-linked amino acid or the optionally substituted N-linked amino acidester derivative can be in the D-configuration.

In some embodiments, R¹⁴ and R¹⁵ can each have the structure

wherein each R²⁶ can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆aryl, an optionally substituted C₁₀ aryl and an optionally substitutedaryl(C₁₋₆ alkyl); each R²⁷ can be hydrogen or an optionally substitutedC₁₋₄-alkyl; and each R²⁸ can be selected from hydrogen, an optionallysubstituted C₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, anoptionally substituted aryl, an optionally substituted aryl(C₁₋₆ alkyl)and an optionally substituted C₁₋₆ haloalkyl, or the R²⁶ and the R²⁷attached to the same carbon can be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl.

In some embodiments, one or both of R²⁶ can be hydrogen. In otherembodiments, one or both of R²⁶ can be an optionally substitutedC₁₋₆-alkyl. Examples of suitable optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). When R²⁶is substituted, R²⁶ can be substituted with one or more substituentsselected from N-amido, mercapto, alkylthio, an optionally substitutedaryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, andamino. In some embodiment, one or both of R²⁶ can be an unsubstitutedC₁₋₆-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl(branched and straight-chained). In an embodiment, one or both of R²⁶can be methyl.

In some embodiments, one or both of R²⁷ can be hydrogen. In otherembodiments, one or both of R²⁷ can be an optionally substituted C₁₋₄alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andtert-butyl. In an embodiment, one or both of R²⁷ can be methyl. In someembodiments, one or both of R²⁶ and R²⁷ attached to the same carbon canbe taken together to form an optionally substituted C₃₋₆ cycloalkyl (forexample, an optionally substituted cyclopropyl, an optionallysubstituted cyclobutyl, an optionally substituted cyclopentyl oroptionally substituted cyclohexyl). Depending on the groups that areselected for R²⁶ and R²⁷, the carbon to which R²⁶ and R²⁷ are attachedmay be a chiral center. In some embodiment, the carbon to which R²⁶ andR²⁷ are attached may be a (R)-chiral center. In other embodiments, thecarbon to which R²⁶ and R²⁷ are attached may be a (S)-chiral center.

In some embodiments, one or both of R²⁸ can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments, one or both of R²⁸ can be an optionally substituted C₃₋₆cycloalkyl. For example, R²⁸ can be an optionally substitutedcyclopropyl, an optionally substituted cyclobutyl, an optionallysubstituted cyclopentyl or an optionally substituted cyclohexyl. Instill other embodiments, one or both of R²⁸ can be an optionallysubstituted aryl, such as optionally substituted phenyl and optionallysubstituted naphthyl. In yet still other embodiments, one or both of R²⁸can be an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments,one or both of R²⁸ can be an optionally substituted benzyl. In someembodiments, one or both of R²⁸ can be an optionally substitutedC₁₋₆haloalkyl, for example, CF₃. In some embodiments, one or both of R²⁸can be hydrogen. In some embodiments, R¹⁴ and R¹⁵ can be the same. Inother embodiments, R¹⁴ and R¹⁵ can be different.

In some embodiments, R¹⁴ can be O⁻, hydroxy or an —O— optionallysubstituted C₁₋₆ alkyl, and R¹⁵ and R⁵ together can be O, such that acompound of Formula (I), or a pharmaceutically acceptable salt thereof,has the structure:

In some embodiments, R¹⁴ can be O⁻. In some embodiments, R¹⁴ can behydroxy. In some embodiments, R¹⁴ can be an —O— optionally substitutedC₁₋₆ alkyl, for example an optionally substituted version of methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy(branched and straight-chained), and hexoxy (branched andstraight-chained). In some embodiments, R¹⁴ can be an —O— unsubstitutedC₁₋₆ alkyl.

In some embodiments, R¹ can be In some embodiment, R¹⁶ can be selectedfrom an —O— optionally substituted aryl, an —O— optionally substitutedheteroaryl and an —O— optionally substituted heterocyclyl, and R¹⁷ canbe an optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative. In some embodiments,R¹⁶ can be an —O— optionally substituted heteroaryl. In otherembodiments, R¹⁶ can be an —O— optionally substituted heterocyclyl. Insome embodiments, R¹⁶ can be an —O— optionally substituted aryl. Forexample, the optionally substituted aryl can be an optionallysubstituted phenyl or an optionally substituted naphthyl. If R¹⁶ is an—O-substituted phenyl or —O-substituted naphthyl, the phenyl andnaphthyl ring can be substituted one or more times. Suitablesubstituents that can be present on optionally substituted phenyl and anoptionally substituted naphthyl include electron-donating groups andelectron-withdrawing groups. In some embodiments, R¹⁶ can be an—O-para-substituted phenyl. In other embodiment, R¹⁶ can be an—O-unsubstituted phenyl or an —O-unsubstituted naphthyl. In someembodiments, R¹⁷ can be an optionally substituted N-linked amino acid oran optionally substituted N-linked amino acid ester derivative of anyone of the following amino acids alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. Suitable esterderivatives include those described herein, such as an optionallysubstituted C₁₋₆ alkyl ester, an optionally substituted C₃₋₆ cycloalkylester, an optionally substituted C₆₋₁₀ aryl ester, and an optionallysubstituted aryl(C₁₋₆ alkyl) ester.

In some embodiments, R¹⁶ and R¹⁷ can each have the structure

wherein each R²⁹ can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆aryl, an optionally substituted C₁₀ aryl and an optionally substitutedaryl(C₁₋₆ alkyl); each R³⁰ can be hydrogen or an optionally substitutedC₁₋₄-alkyl; and each R³¹ can be selected from hydrogen, an optionallysubstituted C₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, anoptionally substituted aryl, an optionally substituted aryl(C₁₋₆ alkyl)and an optionally substituted C₁₋₆ haloalkyl, or the R²⁹ and the R³⁰attached to the same carbon can be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl.

In some embodiments, one or both of R²⁹ can be hydrogen. In otherembodiments, one or both of R²⁹ can be an optionally substitutedC₁₋₆-alkyl. Examples of suitable optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. When R²⁹ issubstituted, R²⁹ can be substituted with one or more substituentsselected from N-amido, mercapto, alkylthio, an optionally substitutedaryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, andamino. In some embodiment, one or both of R²⁹ can be an unsubstitutedC₁₋₆-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl(branched and straight-chained). In an embodiment, one or both of R²⁹can be methyl.

In some embodiments, one or both of R³⁰ can be hydrogen. In otherembodiments, one or both of R³⁰ can be an optionally substitutedC₁₋₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and tert-butyl. In an embodiment, one or both of R³⁰ can bemethyl. In some embodiments, one or both of R²⁹ and R³⁰ attached to thesame carbon can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Depending on the groups that are selected for R²⁹ and R³⁰,the carbon to which R²⁹ and R³⁰ are attached may be a chiral center. Insome embodiment, the carbon to which R²⁹ and R³⁰ are attached may be a(R)-chiral center. In other embodiments, the carbon to which R²⁹ and R³⁰are attached may be a (S)-chiral center.

In some embodiments, one or both of R³¹ can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments, one or both of R³¹ can be an optionally substituted C₃₋₆cycloalkyl. For example, R³¹ can be an optionally substitutedcyclopropyl, an optionally substituted cyclobutyl, an optionallysubstituted cyclopentyl or an optionally substituted cyclohexyl. In someembodiments, R³¹ can be an optionally substituted cyclohexyl. In stillother embodiments, one or both of R³¹ can be an optionally substitutedaryl, such as optionally substituted phenyl and optionally substitutednaphthyl. In yet still other embodiments, one or both of R³¹ can be anoptionally substituted aryl(C₁₋₆ alkyl). In some embodiments, one orboth of R³¹ can be an optionally substituted benzyl. In someembodiments, one or both of R³¹ can be an optionally substituted C₁₋₆haloalkyl, for example, CF₃. In some embodiments, one or both of R³¹ canbe hydrogen. In some embodiments, R¹⁶ and R¹⁷ can be the same. In otherembodiments, R¹⁶ and R¹⁷ can be different.

In some embodiments, R¹⁶ can be O⁻, hydroxy or an —O— optionallysubstituted C₁₋₆ alkyl, and R¹⁷ and R⁵ together can be 0, such that acompound of Formula (I), or a pharmaceutically acceptable salt thereof,has the structure:

In some embodiments, R¹⁶ can be O⁻. In some embodiments, R¹⁶ can behydroxy. In some embodiments, R¹⁶ can be an —O— optionally substitutedC₁₋₆ alkyl, for example an optionally substituted version of methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy(branched and straight-chained), and hexoxy (branched andstraight-chained). In some embodiments, R¹⁶ can be an —O— unsubstitutedC₁₋₆ alkyl.

Examples of suitable

groups include the following:

The substituents attached to the 5′-position of a compound of Formula(I) can vary. In some embodiments, R² and R³ can be the same. In otherembodiments, R² and R³ can be different. In some embodiments, R² and R³can be both hydrogen. In some embodiments, at least of R² and R³ can bean optionally substituted C₁₋₆-alkyl; and the other of R² and R³ can behydrogen. Examples of suitable optionally substituted C₁₋₆ alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, at least one of R² and R³ can be methyl, and the other ofR² and R³ can be hydrogen. In other embodiments, at least of R² and R³can be an optionally substituted C₁₋₆-haloalkyl, and the other of R² andR³ can be hydrogen. One example of a suitable optionally substitutedC₁₋₆-haloalkyl is CF₃. In some embodiments, at least one of R² and R³can be hydrogen; and the other of R² and R³ can be an optionallysubstituted C₁₋₆ alkyl or an optionally substituted C₁₋₆ haloalkyl; andR¹ can be hydrogen. When the substituents attached to the 5′-carbon makethe 5′-carbon chiral, in some embodiments, the 5′-carbon can be a(R)-stereocenter. In other embodiments, the 5′-carbon can be an(S)-stereocenter.

The substituents attached to the 2′-carbon and the 3′-carbon can alsovary. In some embodiments, R⁴ can be hydrogen. In other embodiments, R⁴can be a halogen. Example of halogens include F, C1, Br and I. In stillother embodiments, R⁴ can be an optionally substituted C₁₋₆ alkyl.Examples of suitable optionally substituted C₁₋₆ alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments R⁴ can be —OR¹⁸. When R¹⁸ is hydrogen, R⁴ can be hydroxy.Alternatively, when R¹⁸ is an optionally substituted C₁₋₆ alkyl, R⁴ canbe an optionally substituted C₁₋₆ alkoxy. Suitable alkoxy groups includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, pentoxy (branched and straight-chained), and hexoxy(branched and straight-chained). In some embodiments, R⁴ can be—OC(═O)R¹⁹, in which R¹⁹ can be an optionally substituted C₁₋₆ alkyl.Examples of suitable C₁₋₆ alkyl groups are described herein.

In some embodiments, R⁵ can be hydrogen. In other embodiments, R⁵ can bea halogen, including those described herein. In still other embodiments,R⁵ can be an optionally substituted C₁₋₆ alkyl. In yet still otherembodiments R⁵ can be —OR²⁰. In some embodiments, R⁵ can be —OH. Inother embodiments, R²⁰ can be —OR²⁰, wherein R²⁰ can be an optionallysubstituted C₁₋₆ alkyl. In still other embodiments, R⁵ can be—OC(═O)R²¹, in which R²¹ can be an optionally substituted C₁₋₆ alkyl.Examples of suitable optionally substituted C₁₋₆ alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained).

In some embodiments, R⁶ can be hydrogen. In other embodiments, R⁶ can bea halogen. In still other embodiments, R⁶ can be an optionallysubstituted C₁₋₆ alkyl. In yet still other embodiments R⁶ can be —OR²²,wherein R²² can be hydrogen. In some embodiments, R⁶ can be —OR²²,wherein R²² can be an optionally substituted C₁₋₆ alkyl. Examples ofsubstituents that can be R⁶ include, but are not limited to, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy(branched or straight-chained) and hexoxy (branched orstraight-chained). In some embodiments, R⁶ can be —OC(═O)R²³, whereinR²³ can be an optionally substituted C₁₋₆ alkyl. Examples of suitableC₁₋₆ alkyl groups are described herein. In some embodiments, R⁶ can behydrogen, halogen or —OR²².

In some embodiments, R⁷ can be hydrogen. In other embodiments, R⁷ can bea halogen. In still other embodiments, R⁷ can be an optionallysubstituted C₁₋₆ alkyl. Examples of suitable optionally substituted C₁₋₆alkyls include optionally substituted variants of the following: methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl(branched and straight-chained), and hexyl (branched andstraight-chained). In yet still other embodiments R⁷ can be —OR²⁴,wherein R²⁴ can be hydrogen or an optionally substituted C₁₋₆ alkyl. Anon-limiting list of R⁷ groups include hydroxy, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy(branched and straight-chained), and hexoxy (branched andstraight-chained). In some embodiments, R⁷ can be —OC(═O)R²⁵, whereinR²⁵ can be an optionally substituted C₁₋₆ alkyl, such as those describedherein. In some embodiments, R⁷ is hydrogen or halogen. In someembodiments, R⁷ is —OR²⁴ or an optionally substituted C₁₋₆ alkyl.

In some embodiments, R⁵ and R⁶ can both be hydroxy. In still otherembodiments, R⁵ and R⁶ can both be both oxygen atoms and linked togetherby a carbonyl group, for example, —O—C(═O)—O—. In some embodiments, atleast one of R⁶ and R⁷ can be a halogen. In some embodiments, R⁶ and R⁷can both be a halogen. In some embodiments, R⁶ can be hydroxy and R⁷ canbe a halogen. In other embodiments, R⁵ and R⁶ can be both hydroxygroups, and R⁷ can be a halogen. In still other embodiments, R⁶ can behydrogen and R⁷ can be an optionally substituted C₁₋₆ alkyl. In yetstill other embodiments, at least one of R⁵ and R⁶ can be a hydroxy andR⁷ can be an optionally substituted C₁₋₆ alkyl. In some embodiments, atleast one of R⁵ and R⁶ can be a hydroxy and R⁷ can be a halogen. Forexample, R⁵ can be hydroxy, R⁶ can be a hydrogen and R⁷ can be ahalogen; or R⁵ can be hydrogen, R⁶ can be hydroxy, and R⁷ can be ahalogen; R⁵ can be hydroxy, R⁶ can be hydroxy and R⁷ can be a halogen.In other embodiments, at least one of R⁵ and R⁶ can be an optionallysubstituted C₁₋₆ alkoxy. In some embodiments, R⁵ and R⁷ can be hydroxy,and R⁶ can be hydrogen. In some embodiments, R⁵ can be a hydroxy, andboth R⁶ and R⁷ can be halogen. In some embodiments, R⁵ can be a hydroxyand R⁶ can be halogen.

In some embodiments, R⁸ can be hydrogen. In other embodiments, R⁸ can bean optionally substituted C₁₋₆ alkyl. Examples of R⁸ groups includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In stillother embodiments, can be an optionally substituted C₁₋₆ haloalkyl. Insome embodiments, R⁸ can be CF₃.

Various optionally substituted heterocyclic bases can be attached to thepentose ring. In some embodiments, one or more of the amine and/or aminogroups may be protected with a suitable protecting group. For example,an amino group may be protected by transforming the amine and/or aminogroup to an amide or a carbamate. In some embodiments, an optionallysubstituted heterocyclic base or an optionally substituted heterocyclicbase with one or more protected amino groups can have one of thefollowing structures:

wherein: R^(A2) can be selected from hydrogen, halogen and NHR^(J2),wherein R^(J2) can be selected from hydrogen, —C(═O)R^(K2) and—C(═O)OR^(L2); R^(B2) can be halogen or NHR^(W2), wherein R^(W2) can beselected from hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₃₋₈cycloalkyl, —C(═O)R^(M2) and —C(═O)OR^(N2); R^(C2) can be hydrogen orNHR^(O2), wherein R^(O2) can be selected from hydrogen, —C(═O)R^(P2) and—C(═O)OR^(Q2); R^(D2) can be selected from hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(E2) can beselected from hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₃₋₈ cycloalkyl, —C(═O)R^(R2) and —C(═O)OR^(S2);R^(E2) can be selected from hydrogen, halogen, an optionally substitutedC₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl and an optionallysubstituted C₂₋₆ alkynyl; Y² can be N (nitrogen) or CR^(I2), whereinR^(I2) can be selected from hydrogen, halogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₂₋₆-alkenyl and an optionallysubstituted C₂₋₆-alkynyl; R^(G2) can be an optionally substituted C₁₋₆alkyl; R^(H2) can be hydrogen or NHR^(T2), wherein R^(T2) can beindependently selected from hydrogen, —C(═O)R^(U2) and —C(═O)OR^(V2),R^(Y2) can be hydrogen or NHR^(Z2), wherein R^(Z2) can be selected fromhydrogen, —C(═O)R^(AA2) and —C(═O)OR^(BB2); and R^(K2), R^(L2), R^(M2),R^(N2), R^(P2), R^(Q2), R^(R2), R^(S2), R^(U2), R^(V2), R^(AA2) andR^(BB2) can be independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₆ cycloalkynyl,C₆₋₁₀ aryl, heteroaryl, heteroalicyclyl, aryl(C₁₋₆ alkyl),heteroaryl(C₁₋₆ alkyl) and heteroalicyclyl(C₁₋₆ alkyl). In someembodiments, the structures shown above can be modified by replacing oneor more hydrogens with substituents selected from the list ofsubstituents provided for the definition of “substituted.”

In some embodiments, B¹ can be

In other embodiments, B¹ can be

In still other embodiments, B¹ can be

such as

In yet still other embodiments, B¹ can be

for example,

In some embodiments, R^(D2) can be hydrogen. In other embodiments, B¹can be

In some embodiments, R^(B2) can be NH₂. In other embodiments, R^(B2) canbe NHR^(W2), wherein R^(W2) can be —C(═O)R^(M2) or —C(═O)OR^(N2). Instill other embodiments, B¹ can be

In some embodiments, B¹ can be

In other embodiments, when R², R³, R⁴, and R⁸ are all hydrogen, then R¹cannot be hydrogen. In still other embodiments, when R² and R³ arehydrogen, then R¹ cannot be hydrogen. In yet still other embodiments, R¹cannot be hydrogen. In some embodiments, R¹ cannot be hydrogen when B¹is adenine, guanine, 5-methyluracil, uracil or cytosine. In otherembodiments, when R² and R³ are hydrogen and at least one of R⁵ and R⁶is hydroxy, alkoxy or aryloxy, then R¹ cannot be hydrogen.

In some embodiments, when R² and R³ are both hydrogen, R⁵ is hydroxy, R⁴and R⁶ are both hydrogen, R⁷ is halogen, R⁸ is hydrogen, and B¹ is

then R¹ cannot be

wherein, n is 0 or 2; and R⁹, R¹⁰, and each R¹¹ are absent or hydrogen.In other embodiments, when R² and R³ are both hydrogen, at least one ofR⁵ and R⁶ are hydroxy, and B¹ is

then R¹ cannot be

wherein, n is 0, 1 or 2; and R⁹, R¹⁰, and each R¹¹ are independentlyabsent or hydrogen. In still other embodiments, when R² and R³ are bothhydrogen, at least one of R⁵ and R⁶ are hydroxy, then R¹ cannot be

wherein, n is 0, 1 or 2; and R⁹, R¹⁰, and each R¹¹ are independentlyabsent or hydrogen. In yet still other embodiments, when at least one ofR⁵ and R⁶ are hydroxy, then R¹ cannot be

wherein, n is 0, 1 or 2; and R⁹, R¹⁰, and each R¹¹ are independentlyabsent or hydrogen. In some embodiments, R¹ cannot be

wherein, n is 0; and R⁹ and R¹⁰ are independently absent or hydrogen. Inother embodiments, R¹ cannot be

wherein, n is 1; and R⁹, R¹⁰, and R¹¹ are independently absent orhydrogen. In still other embodiments, R¹ cannot be

wherein, n is 2; and R⁹, R¹⁰, and each R¹¹ are independently absent orhydrogen. In still other embodiments, when at least one of R² and R³ isan optionally substituted C₁₋₆ alkyl, at least one of R⁵ and R⁶ arehydroxy, then R¹ cannot be

wherein, n is 0, 1 or 2; and R⁹, R¹⁰, and each R¹¹ are independentlyabsent or hydrogen. In yet still other embodiments, B¹ cannot be adenineor an optionally substituted adenine when at least one of R² and R³ isnot hydrogen. In some embodiments, when at least one of R² and R³ is anoptionally substituted C₁₋₆ alkyl, then B¹ cannot be an optionallysubstituted adenine or an optionally substituted adenine with one ormore protected amino groups.

In some embodiments, when R¹ is

R² and R³ are both hydrogen, R⁴ is hydrogen, R⁵ is OH, R⁶ is selectedfrom halogen, hydrogen, and hydroxy, R⁷ is selected from halogen,hydrogen, methyl, and hydroxy, R⁸ is hydrogen, B¹ is selected from

R¹⁴ is an —O— optionally substituted aryl, then R¹⁵ cannot be

wherein R²⁶ is selected from hydrogen and C₁₋₄ alkyl; R²⁷ is selectedfrom hydrogen, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CH₂SCH₃,—CH₂CH₂C(═O)OCH₂CH₃, —CH₂C(═O)OCH₂CH₃, —CH₂-indol-3-yl, —CH₂phenyl,unsubstituted cyclopentyl and —CH(CH₂CH₃)CH₃; and R²⁸ is selected fromunsubstituted C₁₋₄-alkyl, and unsubstituted benzyl and CH₂CF₃; In someembodiments, when B¹ is selected from

and R¹⁴ is an —O— optionally substituted aryl, then R¹⁵ cannot be

wherein R²⁶ is selected from hydrogen and an optionally substituted C₁₋₄alkyl; R²⁷ is selected from hydrogen, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂CH₂SCH₃, —CH₂CH₂C(═O)OCH₂CH₃, —CH₂C(═O)OCH₂CH₃,—CH₂C(═O)OCH(CH₃)₂, —CH₂-indol-3-yl, —CH₂phenyl, cyclopentyl and—CH(CH₂CH₃)CH₃; and R²⁸ is selected from an optionally substitutedC₁₋₄-alkyl and an optionally substituted benzyl. In other embodiments,when R¹ is

R², R³, R⁴, R⁷, and R⁸ are all hydrogen, R⁵ is hydroxy, R⁶ is hydroxy,R¹⁴ is —O— naphthyl, R¹⁵ is

wherein R²⁶ is hydrogen, R²⁷ is methyl and R²⁸ is benzyl, then B¹ cannotbe

or

In still other embodiments, when R¹ is

R², R³, R⁴, R⁷ and R⁸ are all hydrogen, R⁵ is hydroxy, R⁶ is hydroxy,R¹⁴ is —O-phenyl, R¹⁵ is

wherein R²⁶ and R²⁷ are taken together to form an substitutedcyclopentyl ring and R²⁸ is a C₁₋₄ alkyl or benzyl, then B¹ cannot be

In yet still other embodiments, when R² and R³ are hydrogen, then R¹cannot be

In some embodiments, R¹ can be

when at least one of R² and R³ is an optionally substituted C₁₋₆ alkylor an optionally substituted C₁₋₆ haloalkyl. In other embodiments, R¹cannot be

In still other embodiments, when R² and R³ are hydrogen, and at leastone of R⁵ and R⁶ are hydroxy, then R¹ cannot be

In yet still other embodiments, when R⁵ is hydroxy, R¹ cannot be

In some embodiments, at least one of R² and R³ cannot be hydrogen. Insome embodiments, at least of one of R⁵ and R⁶ cannot hydroxy. Forexample, R⁵ cannot be hydroxy, R⁶ cannot be hydroxy, or both of R⁵ andR⁶ cannot be hydroxy.

Methods of Use:

Some embodiments described herein relate to a method of ameliorating,treating and/or preventing a viral infection selected from aparamyxovirus viral infection and an orthomyxovirus viral infection,which can include administering a therapeutically effective amount of acompound of Formula (II), or a pharmaceutically acceptable salt thereof:

wherein B^(1a) can be selected from an optionally substitutedheterocyclic base and an optionally substituted heterocyclic base with aprotected amino group; R^(1a) can be selected from hydrogen, anoptionally substituted acyl

n^(a) can be 0, 1 or 2; R^(2a) and R^(3a) can be independently selectedhydrogen, an optionally substituted C₁₋₆ alkyl and an optionallysubstituted C₁₋₆ haloalkyl; R^(4a) can be selected hydrogen, halogen,optionally substituted C₁₋₆ alkyl, —OR^(18a) and —OC(═O)R^(19a); R^(5a)can be selected from hydrogen, halogen, optionally substituted C₁₋₆alkyl, —OR^(20a) and —OC(═O)R^(21a), or when R^(1a) is

and R^(14a) is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl,then R^(15a) and R^(5a) together can be 0, or when R^(1a) is

and R^(16a) is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl,then R^(17a) and R^(5a) together can be O; R^(6a) can be selected fromhydrogen, halogen, optionally substituted C₁₋₆ alkyl, —OR^(22a) and—OC(═O)R^(23a); or R^(5a) and R^(6a) can be both oxygen atoms and linkedtogether by a carbonyl group; R^(7a) can be selected from hydrogen,halogen, optionally substituted C₁₋₆ alkyl, —OR^(24a) and—OC(═O)R^(25a); R^(8a) can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl and an optionally substituted C₁₋₆ haloalkyl;R^(9a), R^(10a), each R^(11a), R^(12a) and R^(13a) can be independentlyabsent or hydrogen; R^(14a) can be selected from an —O— optionallysubstituted aryl, an —O— optionally substituted heteroaryl and an —O—optionally substituted heterocyclyl, and R^(l5a) can be an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative; or R^(14a) can be an optionally substitutedN-linked amino acid or an optionally substituted N-linked amino acidester derivative, and R^(15a) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative; or R^(14a) can be O⁻, hydroxy or an —O— optionallysubstituted C₁₋₆ alkyl, and R^(15a) and R^(5a) together can be O;R^(16a) can be selected from an —O— optionally substituted aryl, an —O—optionally substituted heteroaryl and an —O— optionally substitutedheterocyclyl, and R^(17a) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative; or R^(16a) can be an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivative,and R^(17a) can be an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative; or R^(16a)can be O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl, andR^(17a) and R^(5a) together can be O; R^(18a), R^(20a), R^(22a) andR^(24a) can be independently hydrogen or an optionally substituted C₁₋₆alkyl; and R^(19a), R^(21a), R^(23a) and R^(25a), can be independentlyan optionally substituted C₁₋₆ alkyl.

Other embodiments described herein relate to a method of inhibitingviral replication of a virus selected from a paramyxovirus and anorthomyxovirus, which can include contacting a cell infected with thevirus with an effective amount of a compound of Formula (II) (includinga compound of Formula (IIa), or a pharmaceutically acceptable saltthereof.

In some embodiments, the paramyxovirus viral infection can be arespiratory syncytial viral infection. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(II), or a pharmaceutically acceptable salt thereof, (including acompound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used to treat and/or ameliorate a respiratory syncytialviral infection. For example, the respiratory syncytial viral infectioncan be from an infection by a type RSV A strain and/or a type RSV Bstrain. In some embodiments, a therapeutically effective amount of oneor more compounds of Formula (II), or a pharmaceutically acceptable saltthereof, (including a compound of Formula (IIa), or a pharmaceuticallyacceptable salt thereof) can be used to prevent a respiratory syncytialviral infection. In some embodiments, an effective amount of one or morecompounds of Formula (II), or a pharmaceutically acceptable saltthereof, (including a compound of Formula (IIa), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication arespiratory syncytial virus. In some embodiments, a therapeuticallyeffective amount of one or more compounds of Formula (II), or apharmaceutically acceptable salt thereof, (including a compound ofFormula (IIa), or a pharmaceutically acceptable salt thereof) can beused to inhibit the RSV polymerase complex. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(II), or a pharmaceutically acceptable salt thereof, (including acompound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate an upper respiratory viralinfection caused by a RSV virus infection. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(II), or a pharmaceutically acceptable salt thereof, (including acompound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate a lower respiratory viralinfection caused by a RSV virus infection. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(II), or a pharmaceutically acceptable salt thereof, (including acompound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate one or more symptoms of aRSV virus infection (such as those described herein). In someembodiments, a therapeutically effective amount of one or more compoundsof Formula (II), or a pharmaceutically acceptable salt thereof,(including a compound of Formula (IIa), or a pharmaceutically acceptablesalt thereof) can be used treat and/or ameliorate bronchiolitis and/ortracheobronchitis due to a RSV virus infection. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(II), or a pharmaceutically acceptable salt thereof, (including acompound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate pneumonia due to a RSVinfection. In some embodiments, a therapeutically effective amount ofone or more compounds of Formula (II), or a pharmaceutically acceptablesalt thereof, (including a compound of Formula (IIa), or apharmaceutically acceptable salt thereof) can be used treat and/orameliorate coup due to a RSV virus infection.

In some embodiments, the orthomyxovirus viral infection can be aninfluenza viral infection. In some embodiments, a therapeuticallyeffective amount of one or more compounds of Formula (II), or apharmaceutically acceptable salt thereof, (including a compound ofFormula (IIa), or a pharmaceutically acceptable salt thereof) can beused to prevent an influenza viral infection. In some embodiments, aneffective amount of one or more compounds of Formula (II), or apharmaceutically acceptable salt thereof, (including a compound ofFormula (IIa), or a pharmaceutically acceptable salt thereof) can beused to inhibit the replication an influenza virus. In some embodiments,a therapeutically effective amount of one or more compounds of Formula(II), or a pharmaceutically acceptable salt thereof, (including acompound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used to inhibit the influenza polymerase complex. Insome embodiments, the influenza viral infection can be an influenza Aviral infection. In other embodiments, the influenza viral infection canbe an influenza B viral infection. In some embodiments, a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, (includinga compound of Formula (IIa), or a pharmaceutically acceptable saltthereof) can be used to treat and/or ameliorate one or more subtypes ofinfluenza. For example, a compound of Formula (II), or apharmaceutically acceptable salt thereof, (including a compound ofFormula (IIa), or a pharmaceutically acceptable salt thereof), can beused to treat H1N1 and/or H3N2.

In some embodiments, a therapeutically effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,can be used to treat and/or ameliorate a respiratory syncytial viralinfection. In other embodiments, a therapeutically effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, can be used to treat and/or ameliorate an influenza viralinfection. In some embodiments, a therapeutically effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, can be used to prevent a respiratory syncytial viralinfection. In other embodiments, a therapeutically effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, can be used to prevent an influenza viral infection. Insome embodiments, a therapeutically effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,can be used to inhibit the replication a respiratory syncytial virus. Insome embodiments, a therapeutically effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,can be used to inhibit the replication an influenza virus. In someembodiments, a therapeutically effective amount of one or more compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, can beused to inhibit the RSV polymerase complex. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, can be used toinhibit the influenza polymerase complex. In some embodiments, atherapeutically effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, can be used treatand/or ameliorate an upper respiratory viral infection caused by a RSVvirus infection. In some embodiments, a therapeutically effective amountof one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be used treat and/or ameliorate a lowerrespiratory viral infection caused by a RSV virus infection. In someembodiments, a therapeutically effective amount of one or more compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, can beused treat and/or ameliorate one or more symptoms of a RSV virusinfection (such as those described herein). In some embodiments, atherapeutically effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, can be used treatand/or ameliorate bronchiolitis and/or tracheobronchitis due to a RSVvirus infection. In some embodiments, a therapeutically effective amountof one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be used treat and/or ameliorate pneumoniadue to a RSV virus infection. In some embodiments, a therapeuticallyeffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, can be used treat and/orameliorate coup due to a RSV virus infection.

In some embodiments, a therapeutically effective amount of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,can be used to prevent an influenza viral infection. In someembodiments, the influenza viral infection can be an influenza A viralinfection. In other embodiments, the influenza viral infection can be aninfluenza B viral infection. In some embodiments, a compound of Formula(I), or a pharmaceutically acceptable salt thereof, can be used to treatand/or ameliorate one or more subtypes of influenza. For example, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used to treat H1N1 and/or H3N2. The one or more compounds ofFormula (I) or a pharmaceutically acceptable salt thereof, that can beused to treat, ameliorate and/or prevent a paramyxovirus and/or or anorthomyxovirus viral infection can be a compound of Formula (I), orpharmaceutically acceptable salt thereof, provided in any of theembodiments described in paragraphs [0082]-[0117].

In some embodiments, R^(1a) can be hydrogen. In some embodiments, R^(1a)can be an optionally substituted acyl. For example, R^(1a) can be—C(═O)H, —C(═O)— an optionally substituted alkyl, —C(═O)— an optionallysubstituted alkenyl, —C(═O)— an optionally substituted alkynyl, or—C(═O)— an optionally substituted aryl. In some embodiments, —C(═O)— anoptionally substituted alkyl can be an —C(═O)— an optionally substitutedC₁₋₆ alkyl. In other embodiments, —C(═O)— an optionally substitutedalkenyl can be an —C(═O)— an optionally substituted C₂₋₆ alkenyl. Instill other embodiments, —C(═O)— an optionally substituted alkynyl canbe an —C(═O)— an optionally substituted C₂₋₆ alkynyl. In yet still otherembodiments, —C(═O)— an optionally substituted aryl can be an —C(═O)— anoptionally substituted C₆₋₁₀ aryl.

In some embodiments, R^(1a) can be

wherein n^(a) can be 0, 1 or 2. Those skilled in the art understand thatwhen n is 0, R^(1a) can be a mono-phosphate. Likewise, when n^(a) is 1or 2, those skilled in the art understand R^(1a) can be a di-phosphateor a tri-phosphate, respectively. In some embodiments, at least one ofR^(9a), R^(10a) and each R^(11a) can be absent. Those skilled in the artunderstand that when R^(9a), R^(10a) and/or each R^(11a) is absent, theoxygen associated with R^(9a), R^(10a) and/or each R^(11a) can have anegative charge, which can be denoted as O⁻. In some embodiments, atleast one of R^(9a), R^(10a) and each R^(11a) can be hydrogen. In someembodiments, n^(a) can be 0, and R^(9a) and R^(10a) can be both absent.In other embodiments, n^(a) can be 0, and R^(9a) and R^(10a) can be bothhydrogen. In some embodiments, n^(a) can be 1, and R^(9a), R^(10a) andR^(11a) can be absent. In other embodiments, n^(a) can be 1, and R^(9a),R^(10a) and R^(11a) can be hydrogen. In some embodiments, n^(a) can be2, and R^(9a), R^(10a) and each R^(11a) can be absent. In otherembodiments, n^(a) can be 2, and R^(9a), R^(10a) and each R^(11a) can beboth hydrogen.

In some embodiments, R^(1a) can be

In some embodiments, at least one of R^(12a) and R^(13a) can be bothabsent. For example, R^(12a) can be absent, R^(13a) can be absent orR^(12a) and R^(13a) can be absent. Those skilled in the art understandthat when R^(12a)/R^(13a) are absent, the oxygen associated withR^(12a)/R^(13a) can have a negative charge. In some embodiments, atleast one of R^(12a) and R^(13a) can be hydrogen. Examples of at leastone of R^(12a) and R^(13a) being hydrogen include the following:

In some embodiments, R^(12a) and R^(13a) can be hydrogen.

In some embodiments, R^(1a) can be

In some embodiment, R^(14a) can be selected from an —O— optionallysubstituted aryl, an —O— optionally substituted heteroaryl and an —O—optionally substituted heterocyclyl, and R^(15a) can be an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative. Various amino acids and amino acid esterderivatives can be used, including those described herein. In someembodiments, R^(15a) can be an optionally substituted N-linked α-aminoacid. Suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. In otherembodiments, R^(15a) can be an optionally substituted N-linked α-aminoacid ester derivative. For example, R^(15a) can be an ester derivativeof any of the following amino acids: alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. In some embodiment,R^(15a) can be an ester derivative of alanine. In some embodiments, theester of the optionally substituted N-linked amino acid ester derivativecan be a C₁₋₆ alkyl ester. In other embodiments, the ester of theoptionally substituted N-linked amino acid ester derivative can be aC₃₋₆ cycloalkyl ester. In some embodiments, the optionally substitutedN-linked amino acid or the optionally substituted N-linked amino acidester derivative can be in the L-configuration. In other embodiments,the optionally substituted N-linked amino acid or the optionallysubstituted N-linked amino acid ester derivative can be in theD-configuration.

In some embodiments, R^(15a) can have the structure:

wherein R^(26a) can be selected from hydrogen, an optionally substitutedC₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, anoptionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆alkyl); R^(27a) can be hydrogen or an optionally substituted C₁₋₄-alkyl;and R^(28a) can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted C₁₋₆ haloalkyl, or R^(26a) and R^(27a) can betaken together to form an optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, R^(26a) can be hydrogen. In other embodiments,R^(26a) can be an optionally substituted C₁₋₆-alkyl. Examples ofsuitable optionally substituted C₁₋₆-alkyls include optionallysubstituted variants of the following: methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). WhenR^(26a) is substituted, R^(26a) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy, and amino. In some embodiment, R^(26a) can be anunsubstituted C₁₋₆-alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained),and hexyl (branched and straight-chained). In an embodiment, R^(26a) canbe methyl.

In some embodiments, R^(27a) can be hydrogen. In other embodiments,R^(27a) can be an optionally substituted C₁₋₄-alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In anembodiment, R^(27a) can be methyl. In some embodiments, R^(26a) andR^(27a) can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Depending on the groups that are selected for R^(26a) andR^(27a), the carbon to which R^(26a) and R^(27a) are attached may be achiral center. In some embodiment, the carbon to which R^(26a) andR^(27a) are attached may be a (R)-chiral center. In other embodiments,the carbon to which R^(26a) and R^(27a) are attached may be a (S)-chiralcenter.

As to R^(28a), in some embodiments, R^(28a) can be an optionallysubstituted C₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments, R^(28a) can be an optionally substituted C₃₋₆ cycloalkyl.For example, R^(28a) can be an optionally substituted cyclopropyl, anoptionally substituted cyclobutyl, an optionally substituted cyclopentylor an optionally substituted cyclohexyl. In some embodiments, R^(28a)can be an optionally substituted cyclohexyl. In still other embodiments,R^(28a) can be an optionally substituted aryl, such as optionallysubstituted phenyl and optionally substituted naphthyl. In yet stillother embodiments, R^(28a) can be an optionally substituted aryl(C₁₋₆alkyl). In some embodiments, R^(28a) can be an optionally substitutedbenzyl. In some embodiments, R^(28a) can be an optionally substitutedC₁₋₆ haloalkyl, for example, CF₃. In some embodiments, R^(28a) can behydrogen.

In some embodiments, R^(14a) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative, and R^(15a) can be an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivative.Various amino acids and amino acid ester derivatives can be used,including those described herein. In some embodiments, one or both ofR^(14a) and R^(15a) can be an optionally substituted N-linked α-aminoacid. Suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. In otherembodiments, one or both of R^(14a) and R^(15a) can be an optionallysubstituted N-linked α-amino acid ester derivative. For example, R^(14a)and/or R^(15a) can be an ester derivative of any of the following aminoacids: alanine, asparagine, aspartate, cysteine, glutamate, glutamine,glycine, proline, serine, tyrosine, arginine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, threonine, tryptophan andvaline. In some embodiment, one or both of R^(14a) and R^(15a) can be anester derivative of alanine. In some embodiments, one or both of R^(14a)and R^(15a) can be an optionally substituted N-linked amino acid C₁₋₆alkyl ester derivative. In other embodiments, one or both of R^(14a) andR^(15a) can be an optionally substituted N-linked amino acid C₃₋₆cycloalkyl ester derivative. In some embodiments, the optionallysubstituted N-linked amino acid or the optionally substituted N-linkedamino acid ester derivative can be in the L-configuration. In otherembodiments, the optionally substituted N-linked amino acid or theoptionally substituted N-linked amino acid ester derivative can be inthe D-configuration.

In some embodiments, R^(14a) and R^(15a) can each have the structure

wherein each R^(26a) can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆aryl, an optionally substituted C₁₀ aryl and an optionally substitutedaryl(C₁₋₆ alkyl); each R^(27a) can be hydrogen or an optionallysubstituted C₁₋₄-alkyl; and each R^(28a) can be selected from hydrogen,an optionally substituted C₁₋₆-alkyl, an optionally substituted C₃₋₆cycloalkyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₆ alkyl) and an optionally substituted C₁₋₆ haloalkyl, or theR^(26a) and the R^(27a) attached to the same carbon can be takentogether to form an optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, one or both of R^(26a) can be hydrogen. In otherembodiments, one or both of R^(26a) can be an optionally substitutedC₁₋₆-alkyl. Examples of suitable optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, pentyl (branchedand straight-chained), and hexyl (branched and straight-chained). WhenR^(26a) is substituted, R^(26a) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy, and amino. In some embodiment, one or both of R^(26a) can bean unsubstituted C₁₋₆-alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, and tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In anembodiment, one or both of R^(26a) can be methyl.

In some embodiments, one or both of R^(27a) can be hydrogen. In otherembodiments, one or both of R^(27a) can be an optionally substitutedC₁₋₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and tert-butyl. In an embodiment, one or both of R^(27a) can bemethyl. In some embodiments, one or both of R^(26a) and R^(27a) attachedto the same carbon can be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl. Depending on the groups that are selectedfor R^(26a) and R^(27a), the carbon to which R^(26a) and R^(27a) areattached may be a chiral center. In some embodiment, the carbon to whichR^(26a) and R^(27a) are attached may be a (R)-chiral center. In otherembodiments, the carbon to which R^(26a) and R^(27a) are attached may bea (S)-chiral center.

In some embodiments, one or both of R^(28a) can be an optionallysubstituted C₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments, one or both of R^(28a) can be an optionally substitutedC₃₋₆ cycloalkyl. For example, R^(28a) can be an optionally substitutedcyclopropyl, an optionally substituted cyclobutyl, an optionallysubstituted cyclopentyl or an optionally substituted cyclohexyl. In someembodiments, R^(28a) can be an optionally substituted cyclohexyl. Instill other embodiments, one or both of R^(28a) can be an optionallysubstituted aryl, such as optionally substituted phenyl and optionallysubstituted naphthyl. In yet still other embodiments, one or both ofR^(28a) can be an optionally substituted aryl(C₁₋₆ alkyl). In someembodiments, one or both of R^(28a) can be an optionally substitutedbenzyl. In some embodiments, one or both of R^(28a) can be an optionallysubstituted C₁₋₆ haloalkyl, for example, CF₃. In some embodiments, oneor both of R^(28a) can be hydrogen. In some embodiments, R^(14a) andR_(15a) can be the same. In other embodiments, R^(14a) and R_(15a) canbe different.

In some embodiments, R^(14a) can be O⁻, hydroxy or an —O— optionallysubstituted C₁₋₆ alkyl, and R^(15a) and R^(5a) together can be O, suchthat a compound of Formula (II), or a pharmaceutically acceptable saltthereof, has the structure:

In some embodiments, R^(14a) can be O⁻. In some embodiments, R^(14a) canbe hydroxy. In some embodiments, R^(14a) can be an —O— optionallysubstituted C₁₋₆ alkyl, for example, an optionally substituted versionof methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, pentoxy (branched and straight-chained), and hexoxy(branched and straight-chained). In some embodiments, R^(14a) can be an—O— unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(1a) can be

In some embodiment, R^(16a) can be selected from an —O— optionallysubstituted aryl, an —O— optionally substituted heteroaryl and an —O—optionally substituted heterocyclyl, and R^(17a) can be an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative. In some embodiments, R^(16a) can be an —O—optionally substituted heteroaryl. In other embodiments, R^(16a) can bean —O— optionally substituted heterocyclyl. In some embodiments, R^(16a)can be an —O— optionally substituted aryl. For example, the —O—optionally substituted aryl can be an —O— optionally substituted phenylor an —O— optionally substituted naphthyl. If R^(16a) is an—O-substituted phenyl or an —O— optionally substituted naphthyl, thephenyl and naphthyl ring can be substituted one or more times. Suitablesubstituents that can be present on an —O— optionally substituted phenyland an —O— optionally substituted naphthyl include electron-donatinggroups and electron-withdrawing groups. In some embodiments, R^(16a) canbe an —O-para-substituted phenyl. In other embodiment, R^(16a) can be an—O— unsubstituted phenyl or an —O-unsubstituted naphthyl. In someembodiments, R^(17a) can be an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivativeof any one of the following amino acids alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. Suitable esterderivatives include those described herein, such as an optionallysubstituted C₁₋₆ alkyl ester, an optionally substituted C₃₋₆ cycloalkylester, an optionally substituted C₆₋₁₀ aryl ester, and an optionallysubstituted aryl(C₁₋₆ alkyl) ester.

In some embodiments, R^(16a) and R^(17a) can each have the structure

wherein each R^(29a) can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆aryl, an optionally substituted C₁₀ aryl and an optionally substitutedaryl(C₁₋₆ alkyl); each R^(30a) can be hydrogen or an optionallysubstituted C₁₋₄-alkyl; and each R^(31a) can be selected from hydrogen,an optionally substituted C₁₋₆-alkyl, an optionally substituted C₃₋₆cycloalkyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₆ alkyl) and an optionally substituted C₁₋₆ haloalkyl, or theR^(29a) and the R^(30a) attached to the same carbon can be takentogether to form an optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, one or both of R^(29a) can be hydrogen. In otherembodiments, one or both of R^(29a) can be an optionally substitutedC₁₋₆-alkyl. Examples of suitable optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). WhenR^(29a) is substituted, R^(29a) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy, and amino. In some embodiment, one or both of R^(29a) can bean unsubstituted C₁₋₆-alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained),and hexyl (branched and straight-chained). In an embodiment, one or bothof R^(29a) can be methyl.

In some embodiments, one or both of R^(30a) can be hydrogen. In otherembodiments, one or both of R^(30a) can be an optionally substitutedC₁₋₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and tert-butyl. In an embodiment, one or both of R^(30a) can bemethyl. In some embodiments, one or both of R^(29a) and R^(30a) attachedto the same carbon can be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl. Depending on the groups that are selectedfor R^(29a) and R^(30a), the carbon to which R^(29a) and R^(30a) areattached may be a chiral center. In some embodiment, the carbon to whichR^(29a) and R^(30a) are attached may be a (R)-chiral center. In otherembodiments, the carbon to which R^(29a) and R^(30a) are attached may bea (S)-chiral center.

In some embodiments, one or both of R^(31a) can be an optionallysubstituted C₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments, one or both of R^(31a) can be an optionally substitutedC₃₋₆ cycloalkyl. For example, R^(31a) can be an optionally substitutedcyclopropyl, an optionally substituted cyclobutyl, an optionallysubstituted cyclopentyl or an optionally substituted cyclohexyl. In someembodiments, R^(31a) can be an optionally substituted cyclohexyl. Instill other embodiments, one or both of R^(31a) can be an optionallysubstituted aryl, such as optionally substituted phenyl and optionallysubstituted naphthyl. In yet still other embodiments, one or both ofR^(31a) can be an optionally substituted aryl(C₁₋₆ alkyl). In someembodiments, one or both of R^(31a) can be an optionally substitutedbenzyl. In some embodiments, one or both of R^(31a) can be an optionallysubstituted C₁₋₆ haloalkyl, for example, CF₃. In some embodiments, oneor both of R^(31a) can be hydrogen. In some embodiments, R^(16a) andR^(17a) can be the same. In other embodiments, R^(16a) and R^(17a) canbe different.

In some embodiments, R^(16a) can be O⁻, hydroxy or an —O— optionallysubstituted C₁₋₆ alkyl, and R^(17a) and R^(5a) together can be O, suchthat a compound of Formula (II), or a pharmaceutically acceptable saltthereof, has the structure:

In some embodiments, R^(16a) can be O⁻. In some embodiments, R^(16a) canbe hydroxy. In some embodiments, R^(16a) can be an —O— optionallysubstituted C₁₋₆ alkyl, for example an optionally substituted version ofmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, pentoxy (branched and straight-chained), and hexoxy(branched and straight-chained). In some embodiments, R^(16a) can be an—O— unsubstituted C₁₋₆ alkyl.

Examples of suitable

groups include the following:

The substituents attached to the 5′-position of a compound of Formula(II) can vary. In some embodiments, R^(2a) and R^(3a) can be the same.In other embodiments, R^(2a) and R^(3a) can be different. In someembodiments, R^(2a) and R^(3a) can be both hydrogen. In otherembodiments, at least one of R^(2a) and R^(3a) cannot be hydrogen. Insome embodiments, at least of R^(2a) and R^(3a) can be an optionallysubstituted C₁₋₆-alkyl; and the other of R^(2a) and R^(3a) can behydrogen. Examples of suitable optionally substituted C₁₋₆ alkylsinclude optionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, at least one of R^(2a) and R^(3a) can be methyl, and theother of R^(2a) and R^(3a) can be hydrogen. In other embodiments, atleast of R^(2a) and R^(3a) can be an optionally substitutedC₁₋₆-haloalkyl, and the other of R^(2a) and R^(3a) can be hydrogen. Oneexample of a suitable optionally substituted C₁₋₆-haloalkyl is CF₃. Insome embodiments, at least one of R^(2a) and R^(3a) can be hydrogen; andthe other of R^(2a) and R^(3a) can be an optionally substituted C₁₋₆alkyl or an optionally substituted C₁₋₆ haloalkyl; and R^(1a) can behydrogen. When the substituents attached to the 5′-carbon make the5′-carbon chiral, in some embodiments, the 5′-carbon can be a(R)-stereocenter. In other embodiments, the 5′-carbon can be an(S)-stereocenter.

The substituents attached to the 2′-carbon and the 3′-carbon can alsovary. In some embodiments, R^(4a) can be hydrogen. In other embodiments,R^(4a) can be a halogen. Example of halogens include F, Cl, Br and I. Instill other embodiments, R^(4a) can be an optionally substituted C₁₋₆alkyl. Examples of suitable optionally substituted C₁₋₆ alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In otherembodiments R^(4a) can be —OR^(18a). When R^(18a) is hydrogen, R^(4a)can be hydroxy. Alternatively, when R^(18a) is an optionally substitutedC₁₋₆ alkyl, R^(4a) can be an optionally substituted C₁₋₆ alkoxy.Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched andstraight-chained), and hexoxy (branched and straight-chained). In someembodiments, R^(4a) can be —OC(═O)R^(19a), in which R^(19a) can be anoptionally substituted C₁₋₆ alkyl. Examples of suitable C₁₋₆ alkylgroups are described herein.

In some embodiments, R^(5a) can be hydrogen. In other embodiments,R^(5a) can be a halogen, including those described herein. In stillother embodiments, R^(5a) can be an optionally substituted C₁₋₆ alkyl.In yet still other embodiments R^(5a) can be —OR^(20a). In someembodiments, R^(5a) can be —OH. In other embodiments, R^(20a) can be—OR^(20a), wherein R^(20a) can be an optionally substituted C₁₋₆ alkyl.In still other embodiments, R^(5a) can be —OC(═O)R^(21a), in whichR^(21a) can be an optionally substituted C₁₋₆ alkyl. Examples ofsuitable optionally substituted C₁₋₆ alkyls include optionallysubstituted variants of the following: methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained).

In some embodiments, R^(6a) can be hydrogen. In other embodiments,R^(6a) can be a halogen. In still other embodiments, R^(6a) can be anoptionally substituted C₁₋₆ alkyl. In yet still other embodiments R^(6a)can be —OR^(22a), wherein R^(22a) can be hydrogen. In some embodiments,R^(6a) can be —OR^(22a), wherein R^(22a) can be an optionallysubstituted C₁₋₆ alkyl. Examples of substituents that can be R^(6a)include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched andstraight-chained), and hexoxy (branched and straight-chained). In someembodiments, R^(6a) can be —OC(═O)R^(23a), wherein R^(23a) can be anoptionally substituted C₁₋₆ alkyl. Examples of suitable C₁₋₆ alkylgroups are described herein. In some embodiments, R^(6a) can behydrogen, halogen or —OR^(22a).

In some embodiments, R^(7a) can be hydrogen. In other embodiments,R^(7a) can be a halogen. In still other embodiments, R^(7a) can be anoptionally substituted C₁₋₆ alkyl. Examples of suitable optionallysubstituted C₁₋₆ alkyls include optionally substituted variants of thefollowing: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl (branched and straight-chained), and hexyl (branchedand straight-chained). In yet still other embodiments R^(7a) can be—OR^(24a), wherein R^(24a) can be hydrogen or a an optionallysubstituted C₁₋₆ alkyl. A non-limiting list of R^(7a) groups includehydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy andtert-butoxy. In some embodiments, R^(7a) can be —OC(═O)R^(25a), whereinR^(25a) can be an optionally substituted C₁₋₆ alkyl, such as thosedescribed herein. In some embodiments, R^(7a) is hydrogen or halogen. Insome embodiments, R^(7a) is —OR^(24a) or an optionally substituted C₁₋₆alkyl.

In some embodiments, R^(5a) and R^(6a) can both be hydroxy. In otherembodiments, at least of one of R^(5a) and R^(6a) cannot hydroxy. Forexample, R^(5a) cannot be hydroxy, R^(6a) cannot be hydroxy, or both ofR^(5a) and R^(6a) cannot be hydroxy. In still other embodiments, R^(5a)and R^(6a) can both be both oxygen atoms and linked together by acarbonyl group, for example, —O—C(═O)—O—. In some embodiments, at leastone of R^(6a) and R^(7a) can be a halogen. In some embodiments, R^(6a)and R^(7a) can both be a halogen. In some embodiments, R^(ha) can behydroxy and R^(7a) can be a halogen. In other embodiments, R^(5a) andR^(6a) can be both hydroxy groups and R^(7a) can be a halogen. In stillother embodiments, R^(6a) can be hydrogen and R^(7a) can be anoptionally substituted C₁₋₆ alkyl. In yet still other embodiments, atleast one of R^(5a) and R^(6a) can be a hydroxy and R^(7a) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, at least one ofR^(5a) and R^(6a) can be a hydroxy and R^(7a) can be a halogen. Forexample, R^(5a) can be hydroxy, R^(6a) can be a hydrogen and R^(7a) canbe a halogen; or R^(5a) can be hydrogen, R^(6a) can be hydroxy andR^(7a) can be a halogen; R^(5a) can be hydroxy, R^(6a) can be hydroxyand R^(7a) can be a halogen. In other embodiments, at least one ofR^(5a) and R^(6a) can be an optionally substituted C₁₋₆ alkoxy. In someembodiments, R^(5a) and R^(7a) can be hydroxy, and R^(6a) can behydrogen. In some embodiments, R^(5a) can be a hydroxy, and both R^(6a)and R^(7a) can be halogen. In some embodiments, R^(5a) can be a hydroxyand R^(6a) can be halogen.

In some embodiments, R^(8a) can be hydrogen. In other embodiments,R^(8a) can be an optionally substituted C₁₋₆ alkyl. Examples of R^(8a)groups include optionally substituted variants of the following: methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl(branched and straight-chained), and hexyl (branched andstraight-chained). In still other embodiments, can be an optionallysubstituted C₁₋₆ haloalkyl. In some embodiments, R^(8a) can be CF₃.

Various optionally substituted heterocyclic bases can be attached to thepentose ring. In some embodiments, one or more of the amine and/or aminogroups may be protected with a suitable protecting group. For example,an amino group may be protected by transforming the amine and/or aminogroup to an amide or a carbamate. In some embodiments, an optionallysubstituted heterocyclic base or an optionally substituted heterocyclicbase with one or more protected amino groups can have one of thefollowing structures:

wherein:

R^(A2a) can be selected from hydrogen, halogen and NHR^(J2a), whereinR^(J2a) can be selected from hydrogen, —C(═O)R^(K2a) and —C(═O)OR^(L2a);R^(B2a) can be halogen or NHR^(W2a), wherein R^(W2a) can be selectedfrom hydrogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₂₋₆ alkenyl, an optionally substituted C₃₋₈ cycloalkyl,—C(═O)R^(M2a) and —C(═O)OR^(N2a); R^(C2a) can be hydrogen or NHR^(O2a),wherein R^(O2a) can be selected from hydrogen, —C(═O)R^(P2a) and—C(═O)OR^(Q2a); R^(D2a) can be selected from hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(E2a) can beselected from hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₃₋₈ cycloalkyl, —C(═O)R^(R2a) and—C(═O)OR^(S2a); R^(F2a) can be selected from hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; Y^(ea) can be N(nitrogen) or CR^(I2a), wherein R^(I2a) can be selected from hydrogen,halogen, an optionally substituted C₁₋₆-alkyl, an optionally substitutedC₂₋₆-alkenyl and an optionally substituted C₂₋₆-alkynyl; R^(G2a) can bean optionally substituted C₁₋₆ alkyl; R^(H2a) can be hydrogen orNHR^(T2a), wherein R^(T2a) can be independently selected from hydrogen,—C(═O)R^(U2a) and —C(═O)OR^(V2a), R^(Y2a) can be hydrogen or NHR^(Z2a),wherein R^(Z2a) can be selected from hydrogen, —C(═O)R^(AA2a) and—C(═O)OR^(BB2a); and R^(K2a), R^(L2a), R^(M2a), R^(N2a), R^(P2a),R^(Q2a), R^(R2a), R^(S2a), R^(U2a), R^(V2a), R^(AA2a) and R^(BB2a) canbe independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₆ cycloalkynyl, C₆₋₁₀ aryl,heteroaryl, heteroalicyclyl, aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl)and heteroalicyclyl(C₁₋₆ alkyl). In some embodiments, the structuresshown above can be modified by replacing one or more hydrogens withsubstituents selected from the list of substituents provided for thedefinition of “substituted.”

In some embodiments, B^(1a) can be

In other embodiments, B^(1a) can be

In still other embodiments, B^(1a) can be

such as

In yet still other embodiments, B^(1a) can be

for example,

In some embodiments, R^(D2a) can be hydrogen. In other embodiments,B^(1a) can be

In some embodiments, R^(B2a) can be NH₂. In other embodiments, R^(B2a)can be NHR^(W2a), wherein R^(W2a) can be —C(═O)R^(M2a) or—C(═O)OR^(N2a). In still other embodiments, B^(1a) can be

In some embodiments, B^(1a) can be

In some embodiments, when R^(14a) is an —O— optionally substituted aryl,an —O— optionally substituted heteroaryl or an —O— optionallysubstituted heterocyclyl; and R^(15a) has the structure:

then R^(26a) and R^(27a) cannot be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl. In some embodiments, when R^(14a) andR^(15a) each have the structure

then one or both of R^(26a) and R^(27a) cannot be taken together to forman optionally substituted C₃₋₆ cycloalkyl. In some embodiments, whenR^(16a) is an —O— optionally substituted aryl, an —O— optionallysubstituted heteroaryl or an —O— optionally substituted heterocyclyl;and R^(17a) has the structure:

then R^(29a) and R^(30a) cannot be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl. In some embodiments, when R^(16a) andR^(17a) each have the structure

then one or both of R^(29a) and R^(30a) cannot be taken together to forman optionally substituted C₃₋₆ cycloalkyl. In other embodiments, R^(1a)cannot be hydrogen.

Some embodiments described herein relate to a compound of Formula (II),or a pharmaceutically acceptable salt thereof, wherein B^(1a) can beselected from an optionally substituted heterocyclic base and anoptionally substituted heterocyclic base with a protected amino group;R^(1a) can be selected from hydrogen,

n^(a) can be 0, 1 or 2; R^(2a) and R^(3a) can be independently selectedfrom hydrogen, an optionally substituted C₁₋₆ alkyl and an optionallysubstituted C₁₋₆ haloalkyl; R^(4a) can be selected from hydrogen,halogen, optionally substituted C₁₋₆ alkyl, —OR^(18a) and—OC(═O)R^(19a); R^(5a) can be selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, —OR^(20a) and —OC(═O)R^(21a); R^(6a)can be selected from hydrogen, halogen, optionally substituted C₁₋₆alkyl, —OR^(22a) and —OC(═O)R^(23a); or R^(5a) and R^(6a) can be bothoxygen atoms and linked together by a carbonyl group; R^(7a) can beselected from hydrogen, halogen, optionally substituted C₁₋₆ alkyl,—OR^(24a) and —OC(═O)R^(25a); R^(5a) can be selected from hydrogen, anoptionally substituted C₁₋₆ alkyl and an optionally substituted C₁₋₆haloalkyl; R^(9a), R^(10a), each R^(11a), R^(12a) and R^(13a) can beindependently absent or hydrogen; R^(14a) and R^(16a) can beindependently selected from an —O— optionally substituted aryl, an —O—optionally substituted heteroaryl and an —O— optionally substitutedheterocyclyl; R^(15a) can be

R^(17a) can be an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative; R^(18a),R^(20a), R^(22a) and R^(24a), can be independently selected fromhydrogen and an optionally substituted C₁₋₆ alkyl; R^(19a), R^(21a),R^(23a) and R^(25a) can be independently selected from an optionallysubstituted C₁₋₆ alkyl and an optionally substituted C₃₋₆ cycloalkyl;R^(26a) can be hydrogen or an optionally substituted C₁₋₄-alkyl; R^(27a)can be selected from hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ haloalkyl, an optionally substituted C₃₋₆cycloalkyl, an optionally substituted C₆ aryl, an optionally substitutedC₁₀ aryl, and an optionally substituted aryl(C₁₋₆ alkyl); and R^(28a)can be selected from hydrogen, an optionally substituted C₁₋₆-alkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₁₀aryl, an optionally substituted aryl(C₁₋₆ alkyl), and an optionallysubstituted haloalkyl, or R^(26a) and R^(27a) can be taken together toform an optionally substituted C₃₋₆ cycloalkyl. Some embodimentsdescribed herein related to a compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein B^(1a) can be selectedfrom an optionally substituted heterocyclic base and an optionallysubstituted heterocyclic base with a protected amino group; R^(1a) canbe selected from hydrogen,

n^(a) can be 0, 1 or 2; R^(2a) and R^(3a) can be independently selectedhydrogen, an optionally substituted C₁₋₆ alkyl and an optionallysubstituted C₁₋₆ haloalkyl; R^(4a) can be selected hydrogen, halogen,optionally substituted C₁₋₆ alkyl, —OR^(18a) and —OC(═O)R^(19a); R^(5a)can be selected from hydrogen, halogen, optionally substituted C₁₋₆alkyl, —OR^(20a) and —OC(═O)R^(21a); R^(6a) can be selected fromhydrogen, halogen, optionally substituted C₁₋₆ alkyl, —OR^(22a) and—OC(═O)R^(23a); or R^(5a) and R^(6a) can be both oxygen atoms and linkedtogether by a carbonyl group; R^(7a) can be selected from hydrogen,halogen, optionally substituted C₁₋₆ alkyl, —OR^(24a) and—OC(═O)R^(25a); R^(8a) can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl and an optionally substituted C₁₋₆ haloalkyl;R^(9a), R^(10a) each R^(11a), R^(12a) and R^(13a) can be independentlyabsent or hydrogen; R^(14a) and R^(16a) can be independently selectedfrom an —O— optionally substituted aryl, an —O— optionally substitutedheteroaryl and an —O— optionally substituted heterocyclyl; R^(15a) andR^(17a) can be independently an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivative;R^(18a), R^(20a), R^(22a) and R^(24a) can be independently hydrogen oran optionally substituted C₁₋₆ alkyl; and R^(19a), R^(21a), R^(23a) andR^(25a) can be independently an optionally substituted C₁₋₆ alkyl.

In some embodiments, the compound of Formula (II) can have the structureof Formula (IIa), or a pharmaceutically acceptable salt thereof:

wherein R^(1a) and B^(1a) can be the same as R^(1a) and B^(1a) of acompound of Formula (II), including embodiments described herein; R^(4a)can be hydrogen or hydroxy; R^(5a) can be hydrogen, halogen or hydroxy;R^(ha) can be hydrogen, halogen, hydroxy or —O—C₁₋₆ alkyl, R^(7A) can behydrogen, halogen, hydroxy or an optionally substituted C₁₋₆ alkyl; andR^(8a) can be hydrogen or methyl. In some embodiments for Formula (IIa),B^(1a) can be a substituted or unsubstituted uracil, a substituted orunsubstituted adenine, a substituted or unsubstituted guanine or asubstituted or unsubstituted cytosine.

Examples of compounds of Formulae (I) and/or (II) include, but are notlimited to, the following (for Formula (I), R^(1a) is R¹ in thecompounds of this paragraph).

Additional examples of compounds of Formulae (I) and/or (II) include,but are not limited to, the following:

As used herein, the terms “prevent” and “preventing,” mean a subjectdoes not develop an infection because the subject has an immunityagainst the infection, or if a subject becomes infected, the severity ofthe disease is less compared to the severity of the disease if thesubject has not been administered/received the compound. Examples offorms of prevention include prophylactic administration to a subject whohas been or may be exposed to an infectious agent, such as aparamyxovirus (e.g., RSV) and/or an orthomyxovirus (e.g., influenza).

As used herein, the terms “treat,” “treating,” “treatment,”“therapeutic,” and “therapy” do not necessarily mean total cure orabolition of the disease or condition. Any alleviation of any undesiredsigns or symptoms of a disease or condition, to any extent can beconsidered treatment and/or therapy. Furthermore, treatment may includeacts that may worsen the patient's overall feeling of well-being orappearance.

The term “therapeutically effective amount” is used to indicate anamount of an active compound, or pharmaceutical agent, that elicits thebiological or medicinal response indicated. For example, atherapeutically effective amount of compound can be the amount needed toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the signs orsymptoms of the disease being treated. Determination of atherapeutically effective amount is well within the capability of thoseskilled in the art, in view of the disclosure provided herein. Thetherapeutically effective amount of the compounds disclosed hereinrequired as a dose will depend on the route of administration, the typeof animal, including human, being treated, and the physicalcharacteristics of the specific animal under consideration. The dose canbe tailored to achieve a desired effect, but will depend on such factorsas weight, diet, concurrent medication and other factors which thoseskilled in the medical arts will recognize.

Various indicators for determining the effectiveness of a method fortreating a paramyxovirus viral infection are known to those skilled inthe art. Example of suitable indicators include, but are not limited to,a reduction in viral load, a reduction in viral replication, a reductionin time to seroconversion (virus undetectable in patient serum), areduction of morbidity or mortality in clinical outcomes, and/or otherindicator of disease response.

In some embodiments, an effective amount of a compound of Formulae (II)and/or (IIa), or a pharmaceutically acceptable salt thereof, is anamount that is effective to reduce viral titers to undetectable levels,for example, to about 1000 to about 5000, to about 500 to about 1000, orto about 100 to about 500 genome copies/mL serum. In some embodiments,an effective amount of a compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, is an amount that is effectiveto reduce viral load compared to the viral load before administration ofthe compound of Formula (II) and/or (IIa), or a pharmaceuticallyacceptable salt thereof. For example, wherein the viral load is measurebefore administration of the compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (II) and/or (IIa), ora pharmaceutically acceptable salt thereof (for example, 1 week aftercompletion). In some embodiments, an effective amount of a compound ofFormula (II) and/or (IIa), or a pharmaceutically acceptable saltthereof, can be an amount that is effective to reduce viral load tolower than about 100 genome copies/mL serum. In some embodiments, aneffective amount of a compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, is an amount that is effectiveto achieve a reduction in viral titer in the serum of the subject in therange of about 1.5-log to about a 2.5-log reduction, about a 3-log toabout a 4-log reduction, or a greater than about 5-log reductioncompared to the viral load before administration of the compound ofFormula (II) and/or (IIa), or a pharmaceutically acceptable saltthereof. For example, wherein the viral load is measure beforeadministration of the compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (II) and/or (IIa), ora pharmaceutically acceptable salt thereof (for example, 1 week aftercompletion).

In some embodiments, a compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, can result in at least a 1, 2,3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in thereplication of a paramyxovirus and/or an orthomyxovirus relative topre-treatment levels in a subject, as determined after completion of thetreatment regime (for example, 1 week after completion). In someembodiments, a compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, can result in a reduction ofthe replication of paramyxovirus and/or an orthomyxovirus relative topre-treatment levels in the range of about 2 to about 5 fold, about 10to about 20 fold, about 15 to about 40 fold, or about 50 to about 100fold. In some embodiments, a compound of Formula (II) and/or (IIa), or apharmaceutically acceptable salt thereof, can result in a reduction ofparamyxovirus replication in the range of 1 to 1.5 log, 1.5 log to 2log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 logmore reduction of paramyxovirus replication compared to the reduction ofparamyxovirus reduction achieved by ribavirin (Virazole®), or mayachieve the same reduction as that of ribavirin (Virazole®) therapy in ashorter period of time, for example, in one week, two weeks, one month,two months, or three months, as compared to the reduction achieved aftersix months of ribavirin (Virazole®) therapy. In some embodiments, acompound of Formula (II) and/or (IIa), or a pharmaceutically acceptablesalt thereof, can result in a reduction of orthomyxovirus replication inthe range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3log, 3 log to 3.5 log or 3.5 to 4 log more reduction of orthomyxovirusreplication compared to the reduction of orthomyxovirus reductionachieved by oseltamivir (Tamiflu®), or may achieve the same reduction asthat of oseltamivir (Tamiflu®) therapy in a shorter period of time, forexample, in one week, two weeks, one month, two months, or three months,as compared to the reduction achieved after six months of oseltamivir(Tamiflu®) therapy.

In some embodiments, an effective amount of a compound of Formula (II)and/or a compound of Formula (II), or a pharmaceutically acceptable saltthereof, is an amount that is effective to achieve a sustained viralresponse, for example, non-detectable or substantially non-detectableparamyxovirus and/or an orthomyxovirus RNA (e.g., less than about 500,less than about 400, less than about 200, or less than about 100 genomecopies per milliliter serum) is found in the subject's serum for aperiod of at least about one week, two weeks, one month, at least abouttwo months, at least about three months, at least about four months, atleast about five months, or at least about six months followingcessation of therapy.

After a period of time, infectious agents can develop resistance to oneor more therapeutic agents. The term “resistance” as used herein refersto a viral strain displaying a delayed, lessened and/or null response toa therapeutic agent(s). For example, after treatment with an antiviralagent, the viral load of a subject infected with a resistant virus maybe reduced to a lesser degree compared to the amount in viral loadreduction exhibited by a subject infected with a non-resistant strain.In some embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, can beadministered to a subject infected with RSV that is resistant to one ormore different anti-RSV agents (for example, ribavirin). In someembodiments, development of resistant RSV strains is delayed whenpatients are treated with a compound of Formula (I), and/or a compoundof Formula (II), or a pharmaceutically acceptable salt thereof, comparedto the development of RSV strains resistant to other RSV drugs. In someembodiments, a compound of Formula (I), and/or a compound of Formula(II), or a pharmaceutically acceptable salt thereof, can be administeredto a subject infected with an influenza virus that is resistant to oneor more different anti-influenza agents (for example, amantadine andrimantadine). In some embodiments, development of resistant influenzastrains is delayed when patients are treated with a compound of Formula(I), and/or a compound of Formula (II), or a pharmaceutically acceptablesalt thereof, compared to the development of influenza strains resistantto other influenza drugs.

In some embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, candecrease the percentage of subjects that experience complications from aRSV viral infection compared to the percentage of subjects thatexperience complication being treated with ribavirin. In someembodiments, a compound of Formula (I), and/or a compound of Formula(II), or a pharmaceutically acceptable salt thereof, can decrease thepercentage of subjects that experience complications from an influenzaviral infection compared to the percentage of subjects that experiencecomplication being treated with oseltamivir. For example, the percentageof subjects being treated with a compound of Formula (I), and/or acompound of Formula (II), or a pharmaceutically acceptable salt thereof,that experience complications can be 10%, 25%, 40%, 50%, 60%, 70%, 80%and 90% less compared to subjects being treated with ribavirin oroseltamivir.

In some embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound described herein,can be used in combination with one or more additional agent(s). In someembodiments, a compound of Formula (I), and/or a compound of Formula(II), or a pharmaceutically acceptable salt thereof, can be used incombination with one or more agents currently used in a conventionalstandard of care for treating RSV. For example, the additional agent canbe ribavirin, palivizumab and RSV-IGIV. For the treatment of RSV,additional agents include but are not limited to ALN-RSV01 (AlnylamPharmaceuticals), BMS-433771(1-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one),RFI-641((4,4″-bis-[4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamine]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-disulfonic-acid)),RSV604((S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]di-azepin-3-yl)-urea),MDT-637((4Z)-2-methylsulfanyl-4-[(E)-3-thiophen-2-ylprop-2-enylidene]-1,3-thiazol-5-one),BTA9881, TMC-353121 (Tibotec), MBX-300, YM-53403(N-cyclopropyl-6-[4-[(2-phenylbenzoyl)amino]benzoyl]-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxamide),motavizumab (Medi-524, Medlmmune), Medi-559, Medi-534 and Medi-557. Insome embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, can be usedin combination with one or more agents currently used in a conventionalstandard of care for treating influenza. For example, the additionalagent can be amantadine, rimantadine, zanamivir and oseltamivir. For thetreatment of influenza, additional agents include but are not limited toperamivir((1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethylbutyl]-4-(diaminomethylideneamino)-2-hydroxycyclopentane-1-carboxylicacid), laninamivir((4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[(1R,2R)-3-hydroxy-2-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid), favipirvir (T-705, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide),fludase (DAS 181, NexBio), ADS-8902 (Adamas Pharmaceuticals), IFN-b(Synairgen), beraprost(4-[2-hydroxy-1-[(E)-3-hydroxy-4-methyloct-1-en-6-ynyl]-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl]butanoicacid) and Neugene®.

In some embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, can beadministered with one or more additional agent(s) together in a singlepharmaceutical composition. In some embodiments, a compound of Formula(I), and/or a compound of Formula (II), or a pharmaceutically acceptablesalt thereof, can be administered with one or more additional agent(s)as two or more separate pharmaceutical compositions. For example, acompound of Formula (I), and/or a compound of Formula (II), or apharmaceutically acceptable salt thereof, can be administered in onepharmaceutical composition, and at least one of the additional agentscan be administered in a second pharmaceutical composition. If there areat least two additional agents, one or more of the additional agents canbe in a first pharmaceutical composition that includes a compound ofFormula (I), and/or a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, and at least one of the other additionalagent(s) can be in a second pharmaceutical composition.

The order of administration of a compound of Formula (I), and/or acompound of Formula (II), or a pharmaceutically acceptable salt thereof,with one or more additional agent(s) can vary. In some embodiments, acompound of Formula (I), and/or a compound of Formula (II), or apharmaceutically acceptable salt thereof, can be administered prior toall additional agents. In other embodiments, a compound of Formula (I),and/or a compound of Formula (II), or a pharmaceutically acceptable saltthereof, can be administered prior to at least one additional agent. Instill other embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, can beadministered concomitantly with one or more additional agent(s). In yetstill other embodiments, a compound of Formula (I), and/or a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, can beadministered subsequent to the administration of at least one additionalagent. In some embodiments, a compound of Formula (I), and/or a compoundof Formula (II), or a pharmaceutically acceptable salt thereof, can beadministered subsequent to the administration of all additional agents.

A potential advantage of utilizing a compound of Formula (I), and/or acompound of Formula (II), or a pharmaceutically acceptable salt of theforegoing, in combination with one or more additional agent(s) describedin paragraph [0168] (including pharmaceutically acceptable salts andprodrugs thereof) may be a reduction in the required amount(s) of one ormore compounds of paragraph [0168] (including pharmaceuticallyacceptable salts and prodrugs thereof) that is effective in treating adisease condition disclosed herein (for example, RSV and/or influenza),as compared to the amount required to achieve same therapeutic resultwhen one or more compounds described in paragraph [0168] (includingpharmaceutically acceptable salts and prodrugs thereof) are administeredwithout a compound of Formula (I), and/or a compound of Formula (II), ora pharmaceutically acceptable salt the foregoing. For example, theamount of a compound described in paragraph [0168] (including apharmaceutically acceptable salt and prodrug thereof), can be lesscompared to the amount of the compound described in paragraph [0168](including a pharmaceutically acceptable salt and prodrug thereof),needed to achieve the same viral load reduction when administered as amonotherapy. Another potential advantage of utilizing a compound ofFormula (I), and/or a compound of Formula (II), or a pharmaceuticallyacceptable salt of the foregoing, in combination with one or moreadditional agent(s) described in paragraph [0168] (includingpharmaceutically acceptable salts and prodrugs thereof) is that the useof two or more compounds having different mechanism of actions cancreate a higher barrier to the development of resistant viral strainscompared to the barrier when a compound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), and/or acompound of Formula (II), or a pharmaceutically acceptable salt theforegoing, in combination with one or more additional agent(s) describedin paragraph [0168] (including pharmaceutically acceptable salts andprodrugs thereof) may include little to no cross resistance between acompound of Formula (I), and/or a compound of Formula (II), or apharmaceutically acceptable salt the foregoing, and one or moreadditional agent(s) described in paragraph [0168] (includingpharmaceutically acceptable salts and prodrugs thereof) thereof;different routes for elimination of a compound of Formula (I), and/or acompound of Formula (II), or a pharmaceutically acceptable salt theforegoing, and one or more additional agent(s) described in paragraph[0168] (including pharmaceutically acceptable salts and prodrugsthereof); little to no overlapping toxicities between a compound ofFormula (I), and/or a compound of Formula (II), or a pharmaceuticallyacceptable salt the foregoing, and one or more additional agent(s)described in paragraph [0168] (including pharmaceutically acceptablesalts and prodrugs thereof); little to no significant effects oncytochrome P450; and/or little to no pharmacokinetic interactionsbetween a compound of Formula (I), or a pharmaceutically acceptable saltthereof, and one or more additional agent(s) described in paragraph[0168] (including pharmaceutically acceptable salts and prodrugsthereof).

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.The dosage may be a single one or a series of two or more given in thecourse of one or more days, as is needed by the subject. In someembodiments, the compounds will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

Synthesis

Compounds of Formula (I) and Formula (II), and those described hereinmay be prepared in various ways. Some compounds of Formulae (I) and (II)can be obtained commercially and/or prepared utilizing known syntheticprocedures. General synthetic routes to the compounds of Formulae (I)and (II), and some examples of starting materials used to synthesize thecompounds of Formulae (I) and (II) are shown and described herein. Theroutes shown and described herein are illustrative only and are notintended, nor are they to be construed, to limit the scope of the claimsin any manner whatsoever. Those skilled in the art will be able torecognize modifications of the disclosed syntheses and to devisealternate routes based on the disclosures herein; all such modificationsand alternate routes are within the scope of the claims.

As shown in Scheme 1, compounds of Formulae (I) and (II) can be preparedfrom a nucleoside, for example, a nucleoside of Formula (A). In Scheme1, R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a) and B^(1a) canbe the same as R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a)and B^(1a) as described herein for Formula (II) for preparing a compoundof Formula (II). For preparing a compound of Formula (I), R^(2a),R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a) and B^(1a) can be thesame as R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and B^(1a) as described herein forFormula (I). The nucleoside can undergo elimination and form an olefinhaving the general formula of Formula (B). A compound of Formula (B) canbe treated with an iodinating reagent in the presence of an azide sourceto form a compound of Formula (C). A compound of Formula (C) can then betransformed to a compound of Formula (I) and/or a compound of Formula(II) through displacement of the iodide with an oxygen nucleophile. Thedisplacement can occur directly or following an in situ oxidation of theiodide of a compound of Formula (C).

Phosphoramidate can be prepared using various methods known to thoseskilled in the art. One method is shown in Scheme 2. In Scheme 2,R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a), R^(14a), R^(15a)and B^(1a) can be the same as R^(2a), R^(3a), R^(4a), R^(5a), R^(6a),R^(7a), R^(8a), R^(14a), R^(15a) and B^(1a) as described herein forFormula (II) for preparing a compound of Formula (II). For preparing acompound of Formula (I), R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a),R^(8a), R^(14a), R^(15a) and B^(1a) can be the same as R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R¹⁴, R¹⁵ and B^(1a) as described herein for Formula (I).

Various methods for preparing a compound of Formula (I) and/or acompound of Formula (II), wherein R¹ is a thiophosphoramidates, areknown by those skilled in the art. For example, a compound of Formula(I) and/or a compound of Formula (II) can be prepared as shown in Scheme3. In Scheme 3, R^(2a), R^(3a), R^(4a), R^(5a), R^(6a), R^(7a), R^(8a),R1 ^(6a), R^(17a) and B^(1a) can be the same as R^(2a), R^(3a), R^(4a),R^(5a), R^(6a), R^(7a), R^(8a), R^(16a), R^(17a) and B^(1a) as describedherein for Formula (II) for preparing a compound of Formula (II). Forpreparing a compound of Formula (I), R^(2a), R^(3a), R^(4a), R^(5a),R^(6a), R^(7a), R^(8a), R^(16a), R^(17a) and B^(1a) can be the same asR², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁶, R¹⁷ and B^(1a) as described herein forFormula (I).

Suitable phosphorochloridates and thiophosphorochloridates can becommercially obtained or prepared by synthetic methods known to thoseskilled in the art. An example of a general structure of aphosphorochloridates and thiophosphorochloridates are shown in Schemes 2and 3, respectively. In some embodiments, the phosphorochloridate or thethiophosphorochloridate can be coupled to a compound of Formula (D). Insome embodiments, to facilitate the coupling, a Grignard reagent can beused. Suitable Grignard reagents are known to those skilled in the artand include, but are not limited to, alkylmagnesium chlorides andalkylmagnesium bromides. In other embodiments, the phosphorochloridateor the thiophosphorochloridate can be added to a compound of Formula (D)using a base. Suitable bases are known to those skilled in the art.Examples of bases include, but are not limited to, an amine base, suchas an alkylamine (including mono-, di- and tri-alkylamines (e.g.,triethylamine)), optionally substituted pyridines (e.g. collidine) andoptionally substituted imidzoles (e.g., N-methylimidazole)).

A method for forming a compound of Formula (I) and/or a compound ofFormula (II), wherein the 5′-carbon is joined to the 3′-carbon is shownin Scheme 4. In Scheme 4, R^(2a), R^(3a), R^(4a), R^(6a), R^(7a),R^(8a), R^(14a), R^(16a) and B^(1a) can be the same as R^(2a), R^(3a),R^(4a), R^(6a), R^(7a), R^(8a), R^(14a), R^(16a) and B^(1a) as describedherein for Formula (II) for preparing a compound of Formula (II), eachL^(l) can be a halogen, a sulfonate ester or an amine (mono- ordi-substituted), and X can be oxygen or sulfur. For preparing a compoundof Formula (I), R^(2a), R^(3a), R^(4a), R^(6a), R^(7a), R^(8a), R^(14a),R^(16a) and B^(1a) can be the same as R², R³, R⁴, R⁶, R⁷, R⁸, R¹⁴, R¹⁶and B^(1a) as described herein for Formula (I). As illustrated in Scheme4, a compound having a hydroxy group attached to the 3′-carbon and ahydroxy group attached to the 5′-carbon can be reacted with a compoundhaving the formula, (R^(14a)/R^(16a))P(L¹)₂, in the presence of a base,to produce a phosphite compound. Suitable bases are known to thoseskilled in the art and described herein. The phosphorus can then beoxidized to phosphorus(V) using a suitable oxidizing agent, to produce acompound where X is O (oxygen). Alternatively, the phosphite compoundcan be reacted with a sulfurization reagent to produce a compound whereX is S (sulfur). Suitable oxidizing and sulfurization agents are knownto those skilled in the art. For example, the oxidation can be carriedout using iodine as the oxidizing agent and water as the oxygen donor.Suitable sulfurization agents include, but are not limited to, elementalsulfur, Lawesson's reagent, cyclooctasulfur,3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage's reagent),3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione(DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

During the synthesis of any of the compounds described herein, ifdesired, any hydroxy groups attached to the pentose ring, and any —NHand/or NH₂ groups present on the B^(lA) can be protected with one ormore suitable protecting groups. Suitable protecting groups aredescribed herein. For example, when R^(5a) and R^(6a) are both hydroxygroups, R^(5a) and R^(6a) can be protected with one or moretriarylmethyl groups, one or more silyl groups or a single achiral orchiral protecting group (for example, by forming an orthoester, cyclicacetal or cyclic ketal). Likewise, any —NH and/or NH₂ groups present onthe B^(1A) can be protected, such as with a triarylmethyl and a silylgroup(s). Examples of triarylmethyl groups include but are not limitedto, trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr),4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy) trityl(TBTr), 4,4′,4″-tris (4,5-dichlorophthalimido) trityl (CPTr),4,4′,4″-tris (levulinyloxy) trityl (TLTr),p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl,p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl,9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox),4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl,9-(4-octadecyloxyphenyl) xanthen-9-yl,1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl,4,4′,4″-tris-(tert-butylphenyl) methyl (TTTr) and 4,4′-di-3,5-hexadienoxytrityl. Examples of silyl groups include, but are notlimited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS),tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.Suitable orthoesters include methoxymethylene acetal, ethoxymethyleneacetal, 2-oxacyclopentylidene orthoester, dimethoxymethylene orthoester,1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester,methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylideneorthoester, and alpha-methoxybenzylidene orthoester; suitable cyclicacetals include methylene acetal, ethylidene acetal, t-butylmethylideneacetal, 3-(benzyloxy)propyl acetal, benzylidene acetal,3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; andsuitable cyclic ketals include 1-t-butylethylidene ketal,1-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal,cyclohexylidene ketal, cycloheptylidene ketal and1-(4-methoxyphenyl)ethylidene ketal. Those skilled in the art willappreciate that groups attached to the pentose ring and any —NH and/orNH₂ groups present on the B^(1A) can be protected with variousprotecting groups, and any protecting groups present can be exchangedfor other protecting groups. The selection and exchange of theprotecting groups is within the skill of those of ordinary skill in theart. Any protecting group(s) can be removed by methods known in the art,for example, with an acid (e.g., a mineral or an organic acid), a baseor a fluoride source.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceuticalcomposition, that can include a therapeutically effective amount of oneor more compounds described herein (e.g., a compound of Formula (I)and/or a compound of Formula (II), or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable carrier, diluent, excipientor combination thereof.

The term “pharmaceutical composition” refers to a mixture of a compounddisclosed herein with other chemical components, such as diluents orcarriers. The pharmaceutical composition facilitates administration ofthe compound to an organism. Pharmaceutical compositions can also beobtained by reacting compounds with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, topical, aerosol, injectionand parenteral delivery, including intramuscular, subcutaneous,intravenous, intramedullary injections, intrathecal, directintraventricular, intraperitoneal, intranasal and intraocularinjections.

One may also administer the compound in a local rather than systemicmanner, for example, via injection of the compound directly into theinfected area, often in a depot or sustained release formulation.Furthermore, one may administer the compound in a targeted drug deliverysystem, for example, in a liposome coated with a tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe organ.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compounddescribed herein formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1 Preparation of 4′-azido-2′-deoxy-2′,2′-difluorocytidine (1)

Step 1. Compound 1-2—

Compound 1-1 (30.0 g, 0.1 mol) was suspended in anhydrous pyridine (300mL) and stirred at room temperature (R.T.) for 1 hour. The suspensionwas cooled to 0° C. and TMSCl (27.3 g, 0.25 mmol) was added dropwise.After addition was complete, the mixture was warmed to R.T. and stirredfor 30 min. The mixture was then re-cooled to 0° C. and BzCl (15.5 g,0.11 mol) was added dropwise. The mixture was warmed to R.T. and stirredovernight. The reaction was cooled to 0° C. and quenched with H₂O.Aqueous ammonia was added, and the reaction was stirred at R.T. for 2hours. The solution was concentrated and the residue was taken up intoethyl acetate (EA) and H₂O. The aqueous phase was extracted with EAseveral times, and the combined organic layers were dried over Na₂SO₄and concentrated. The residue was purified on a silica gel column togive compound 1-2 as a white solid (28.2 g, 76%). ESI-LCMS: m/z=368[M+Na]⁺.

Step 2. Compound 1-3—

To a stirred suspension of compound 1-2 (18.4 g, 50 mmol), PPh₃ (22.3 g,85 mmol) and pyridine (25 mL) in anhydrous THF (300 mL) was added asolution of I₂ (19.05 g, 75 mmol) in THF (80 mL) dropwise at 0° C. Afteraddition, the mixture was warmed to R.T. and stirred for 60 hours. Theprecipitate was removed by filtration, and the filtrate wasconcentrated. The residue was dissolved in dichloromethane (DCM) andwashed with saturated Na₂S₂O₃ aqueous solution and then brine. Theorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified on a silica gel column to afford compound 1-3 (16.4 g, 69%).ESI-LCMS: m/z=478 [M+H]⁺.

Step 3. Compound 1-4—

To a stirred solution of compound 1-3 (17.0 g, 35.6 mmol) in anhydrousdimethylformamide (DMF) (300 mL) was added dropwise a solution of t-BuOK(10.0 g, 89.1 mmol) in DMF (120 mL) at 0° C. over 20 min. Stirring wascontinued at 0° C. for 45 min, and then concentrated hydrochloric acid(4.5 mL) was added. A pH value of 8-9 was achieved by adding a saturatedNaHCO₃ solution. The precipitate was removed by filtration, and thefiltrate was diluted with ethyl acetate. The solution was washed withbrine and dried over Na₂SO₄. The solvent was removed, and the residuewas purified on a silica gel column to afford compound 1-4 as a whitesolid (8.6 g, 69%). ESI-LCMS: m/z=350 [M+H]⁺.

Step 4. Compound 1-5—

To a stirred solution of Bn Et₃NCl (37.4 g, 0.16 mol) in MeCN (600 mL)was added NaN₃ (10.8 g, 0.16 mol). The mixture was sonicated for 20 min,and then stirred at R.T. for 16 hours. The solution was filtrated into asolution of compound 1-4 (11.5 g, 32.9 mmol) and N-methylmorpholine (3.5g) in anhydrous THF (200 mL). The mixture was cooled to 0° C. and asolution of I₂ (33.6 g, 0.14 mol) in THF (100 mL) was added dropwise.Stirring was continued at 0-10° C. for 20 hours. N-Acetyl cystein wasadded until no gas evolved. Saturated Na₂S₂O₃ aq. was added until alight yellow solution was achieved. The solution was concentrated andthen diluted with EA. The organic phase was washed with brine and driedover Na₂SO₄. The solvent was removed, and the residue was purified on asilica gel column to give compound 1-5 (14.7 g, 84%). ESI-LCMS: m/z=519[M+H]⁺.

Step 5. Compound 1-6—

To a stirred solution of compound 1-5 (12.5 g, 24.8 mmol) in anhydrouspyridine (200 mL) was added BzCl (4.3 g, 30 mmol) dropwise at 0° C. Themixture was then stirred at R.T. for 10 hours. The reaction was quenchedwith H₂O, and the solution was concentrated. The residue was dissolvedin EA and washed with saturated NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel columnto give compound 1-6 as a white foam (11.2 g). ESI-LCMS: m/z=623 [M+H]⁺.

Step 6. Compound 1-7—

Compound 1-6 (9.43 g, 15.2 mmol), BzONa (21.9 g, 152 mmol) and15-crown-5 (33.4 g, 152 mmol) were suspended in 200 mL DMF. The mixturewas stirred at 60-70° C. for 3 days. The precipitate was removed byfiltration, and the filtrate was diluted with EA. The solvent was washedwith brine and dried over Na₂SO₄. The solvent was removed, and theresidue was purified on a silica gel column to afford compound 1-7 as awhite foam (4.4 g, 46%). ESI-LCMS: m/z=617 [M+H]⁺.

Step 7. Compound (1)—

Compound 1-7 (4.4 g, 7.13 mmol) was dissolved in 100 mL of saturatedmethanolic ammonia, and the resulting solution was stirred at R.T. for14 hours. The solvent was removed, and the residue was purified on asilica gel column (DCM/MeOH=30:1 to 10:1) to give (1) as a white solid(1.9 g, 88%). ¹H NMR (CD₃OD, 400 M Hz) δ 7.70 (d, J=7.6 Hz, 1H), 6.40(t, J=7.2 Hz, 1H), 5.93 (d, J=7.6 Hz, 1H), 4.50 (t, J=13.2 Hz, 1H), 3.88(dd, J₁=12.0 Hz, J₂=26.8 Hz, 2H); ESI-MS: m/z=305 [M+H]⁺, 609 [2M+H]⁺.

Example 2 Preparation of 4′-azido-2′-deoxy-2′-fluorocytidine (2)

Step 1. Compound 12-2—

To a stirred solution of compound 12-1 (21.0 g, 85.7 mmol) in DMF (100mL) was added benzoyl anhydride (9.66 g, 87 mmol) in portions. Themixture was stirred at R.T. overnight. The solvent was removed underreduced pressure, and the residue was triturated with CH₂Cl₂ to givecompound 12-2 as a white solid (29.90 g, 100%).

Step 2. Compound 12-3—

To a stirred suspension of compound 12-2 (10.0 g, 28.65 mmol), PPh₃(15.01 g, 57.30 mmol) and pyridine (20 mL) in anhydrous THF (100 mL) wasadded dropwise a solution of I₂ (14.55 g, 57.30 mmol) in THF (50 mL) at0° C. After addition. the mixture was warmed to R.T. and stirred for 14hours. The reaction was quenched with saturated aqueous Na₂S₂O₃ (150 mL)and extracted with EA (100 mL, 3 times). The organic layer was driedover Na₂SO₄ and concentrated. The residue was purified on a silica gelcolumn (DCM/MeOH=100:1 to 50:1) to afford compound 12-3 (4.61 g, 35.1%)as a white solid.

Step 3. Compound 12-4—

To a stirred solution of compound 12-3 (4.6 g, 10.02 mmol) in anhydrousDMF (100 mL) was added dropwise a suspension of t-BuOK (3.36 g, 30.06mmol) in DMF (20 mL) at 0° C. over 10 min. The mixture was stirred atR.T. for 2 hours. The mixtures was then quenched with saturated aqueousNH₄Cl (50 mL), and extracted with THF and EA. The organic layer waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (MeOH/DCM=1/100 to 1/30)to afford compound 12-4 as white solid (3.30 g, 99.6%).

Step 4. Compound 12-5—

To a stirred solution of BnEt₃NCl (11.69 g, 50.2 mmol) in MeCN (50 mL)was added NaN₃ (3.26 g, 50.2 mmol). The mixture was sonicated for 20 minand then stirred at R.T. for 16 hours. The solution was filtrated into asolution of compound 12-4 (3.31 g, 10.02 mmol) and NMM (5.02 g, 50.2mmol) in anhydrous THF (80 mL). The mixture was cooled to 0° C., and asolution of I₂ (12.5 g, 50.2 mmol) in THF (40 mL) was added dropwise.Stirring was continued at 0-10° C. for 20 hours. N-Acetyl cystein wasadded until no gas evolved. Saturated aqueous Na₂S₂O₃ was added until alight yellow solution achieved. The solution was concentrated and thendiluted with EA. The organic phase was washed with brine and dried overNa₂SO₄. The solvent was removed, and the residue was purified on asilica gel column (PE:EA:DCM=1:1:1) to give compound 12-5 (14.7 g, 84%)as a white foam. ¹H NMR (CD₃OD, 400 MHz) δ 11.41 (s, 1H), 8.19 (d, J=7.2Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.62-7.66 (m, 1H), 7.50-7.54 (m, 2H),7.39 (d, J=7.2 Hz, 1H), 6.44 (d, J=6.8 Hz, 1H), 6.13 (d, J=20.4 Hz, 1H),5.36-5.41 (m, 1H), 4.70-4.76 (m, 1H), 3.72 (dd, J₁=17.6 Hz, J₂=11.6 Hz,2H).

Step 5. Compound 12-6—

To a stirred solution of compound 12-5 (3.6 g, 7.20 mmol) in anhydrouspyridine (80 mL) was added BzCl (1.31 g, 9.36 mmol) dropwise at 0° C.The mixture was stirred at R.T. for 10 hours. The reaction was quenchedwith H₂O, and the solution was concentrated. The residue was dissolvedin EA and washed with saturated aqueous NaHCO₃. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified on a silicagel column (PE/EA=10/1 to 1/1) to give compound 12-6 (3.2 g, 73.7%) as apale yellow foam.

Step 6. Compound 12-7—

Compound 12-6 (2.0 g, 3.31 mmol), BzONa (4.76 g, 33.1 mmol) and15-crown-5 (7.28 g, 33.1 mmol) were suspended in DMF (100 mL). Themixture was stirred at 60-70° C. for 3 days. The precipitate removed byfiltration, and the filtrate was diluted with EA. The solution waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (PE/EA=4/1 to 2/1) toafford compound 12-7 as a light yellow foam (1.0 g, 50.7%).

Step 7. Compound (2)—

Compound 12-7 (0.5 g, 0.84 mmol) was dissolved in methanolic ammonia (30mL), and the mixture was stirred at R.T. for 14 hours. The solvent wasremoved, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to give (2) as white solids (0.11 g, 41.8%). ¹HNMR (CD₃OD, 400 MHz) δ 7.83 (d, J=7.6 Hz, 1H), 6.10 (dd, J₁=19.6 Hz,J₂=1.6 Hz, 1H), 5.94 (d, J=7.6 Hz, 1H), 5.10 (ddd, J₁=53.6 Hz, J₂=5.2Hz, J₃=1.2 Hz, 1H), 4.57 (t, J=5.2 Hz, 1H), 3.82 (dd, J₁=38.0 Hz,J₂=12.4 Hz, 2H); ESI-MS: m/z=287 [M+H]⁺, 573 [2M+H]⁺.

Example 3 Preparation of 3′-deoxy-3′-alpha-fluoro-4′-azidocytidine (3)

Compound (3) was prepared using the procedure set forth in the Journalof Medicinal Chemistry (2009) 52:2971-2978, which are herebyincorporated by reference for the limited purpose of disclosing theprocedure of preparing (3).

Example 4 Preparation of 4′-azido-3′-deoxycytidine (4)

Compound (4) was prepared using the procedure set forth in the Journalof Medicinal Chemistry (2009) 52:2971-2978, which are herebyincorporated by reference for the limited purpose of disclosing theprocedure of preparing (4).

Example 5 Preparation of 4′-azido-2′-deoxy-2′,2′-difluorouridine (5)

Step 1. Compound 2-1—

Compound 1-7 (860 mg, 1.40 mmol) was dissolved in 80% acetic acid (AcOH)aqueous solution, and the mixture was refluxed for 14 hours. The solventwas removed under reduced pressure. The residue was co-evaporated withtoluene and absorbed on silica gel. The residue was loaded on a silicagel column and eluted with PE/EA=4:1 to 2:1 to give compound 2-1 as awhite foam (520 mg, 72%).

Step 2. Compound (5)—

Compound 2-1 (520 mg, 1.01 mmol) was dissolved in saturated methanolicammonia, and the resulting solution was stirred at R.T. for 12 hours.The solvent was removed, and the residue was purified on a silica gelcolumn (DCM/MeOH=30:1 to 10:1) to give (5) as a white solid (290 mg,95%). ¹H NMR (CD₃OD, 400 MHz) δ7.69 (d, J=8.4 Hz, 1H), 6.30 (t, J=7.2Hz, 1H), 5.74 (d, J=8.4 Hz, 1H), 5.17 (t, J=12.8 Hz, 1H), 3.87 (dd,J₁=12.8 Hz, J₂=26.8 Hz, 2H). ESI-TOF-MS: m/z=306 [M+HH]⁺.

Example 6 Preparation of 4′-azido-2′-deoxy-2′-methylarabinouridine (6)

Step 1. Compound 7-2—

To a stirred solution of compound 7-1 (7.74 g, 11.6 mmol) in anhydrouspyridine (50 mL) was added TIPDSCl₂ (9.45 g, 11.6 mmol) dropwise at 0°C. After addition, the mixture was warmed gradually to R.T. and stirredovernight. The reaction mixture was quenched with H₂O, and the solventwas removed. The residue was dissolved in EA. The organic layer waswashed by saturated aqueous NaHCO₃ (50 mL) twice, dried over Na₂SO₄, andconcentrated to give compound 7-2 (13.7 g, 91.3%) as a white foam.

Step 2. Compound 7-3—

To a stirred solution of compound 7-2 (5.3 g, 10.6 mmol) and DMAP (2.5g, 21.2 mmol) in anhydrous MeCN (100 mL) was added ethyl oxalyl chloride(ClCOCOOEt) (2.16 g, 15.9 mmol) dropwise at 0° C. After addition, themixture was warmed to R.T. gradually and stirred overnight. The reactionmixture was quenched with H₂O. The solution was diluted with EA andwashed with saturated aqueous NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(PE/EA=3:1) to give compound 7-3 (5.9 g, 92.8%) as a white foam.

Step 3. Compound 7-4—

To a stirred solution of compound 7-3 (5.9 g, 9.8 mmol) and AIBN (322mg, 1.97 mmol) in toluene (50 mL) was added n-Bu₃SnH (11.4 g, 39.2mmol). The reaction mixture was refluxed for 5 hours. The solvent wasremoved, and the residue was purified on a silica gel column (PE/EA=4:1)to afford compound 7-4 (4.3 g, 90.3%) as a mixture of 2′-epimers.

Step 4. Compound 7-5—

A mixture of compound 7-4 (4.3 g, 8.87 mmol) and NH₄F (1.85 g, 50 mmol)in anhydrous MeOH (50 mL) was refluxed for 10 hours. The solvent wasremoved under reduced pressure. The residue was purified by columnchromatography (DCM/MeOH=10:1 to 8:1) to give compound 7-5 (1.96 g,91.2%) as a mixture of 2′-epimers with a ratio of 10:1. ¹H NMR for themajor one (CD₃OD, 400 MHz) δ 8.06 (d, J=10.4 Hz, 1H), 6.20 (d, J=19.2Hz, 1H), 6.65 (d, J=10.4 Hz, 1H), 3.83-3.93 (m, 2H), 3.69-3.77 (m, 2H),2.46-2.55 (m, 1H), 0.94 (d, J=8.4 Hz, 3H).

Step 5. Compound 7-6—

To a stirred solution of compound 7-5 (1.96 g, 8.09 mmol), PPh₃ (4.24 g,16.18 mmol) and imidazole (1.10 g, 16.2 mmol) in anhydrous THF (30 mL)was added dropwise a solution of I₂ (3.287 g, 12.94 mmol) in anhydrousTHF (5 ml) at 0° C. After addition, the mixture was warmed to R.T.gradually and stirred overnight. The reaction was quenched withsaturated Na₂S₂O₃, extracted with EA and washed with brine. The organiclayer was dried over Na₂SO₄, concentrated and purified on a silica gelcolumn to give compound 7-6 (2.14 g, 75.1%).

Step 6. Compound 7-7—

To a stirred solution of compound 7-6 (2.14 g, 6.07 mmol) in anhydrousMeOH (100 mL) was added NaOMe (6.56 g, 121.4 mmol) dropwise at 0° C.After addition, the reaction was refluxed for 16 hours. The reaction wasquenched with AcOH (10 ml) and concentrated. The residue was purified ona silica gel column (DCM/MeOH=100:1 to 50:1) to afford compound 7-7(1.21 g, 89.0%) as a white solid.

Step 7. Compound 7-8—

To a stirred solution of BnEt₃NCl (7.44 g, 31.35 mmol) in anhydrous MeCN(30 mL) was added NaN₃ (2.08 g, 32 mmol). The mixture was sonicated for20 min and then stirred at R.T. for 16 hours. The solution was filtratedinto a solution of compound 7-7 (1.21 g, 5.4 mmol) and NMM (6 mL) inanhydrous THF (70 mL). The mixture was cooled to 0° C. and a solution ofI₂ (7.96 g, 31.3 mmol) in THF (20 mL) was added dropwise. The reactionwas stirred at R.T. for 20 hours. N-acetyl cystein was added until nogas evolved. Saturated aqueous Na₂S₂O₃ was added until a light yellowsolution achieved. The solution was concentrated and diluted with EA(100 mL). The organic layer was washed with brine and dried over Na₂SO₄The solvent was removed, and the residue was purified on silica gel togive compound 7-8 (2.01 g, 94.3%) as a pale yellow foam.

Step 8. Compound 7-9—

To a stirred solution of compound 7-8 (2.01 g, 5.12 mmol) in anhydrouspyridine (50 mL) was added BzCl (1.306 g, 10.01 mmol) dropwise at 0° C.The reaction was stirred at R.T. for 12 hours. The reaction was quenchedby saturated NaHCO₃ and extracted with EA. The organic layer was washedwith brine and dried over Na₂SO₄. The organic layer was concentrated andpurified on a silica column (PE/EA=3:1) to give compound 7-9 (1.73 g,68.1%).

Step 9. Compound 7-10—

Compound 7-9 (1.73 g, 3.6 mmol), BzONa (5.183 g, 36 mmol) and 15-crown-5(7.92 g, 36 mmol) were suspended in 100 mL DMF. The mixture was stirredat 90-100° C. for 3 days. The precipitate was removed by filtration, andthe filtrate was diluted with EA. The solvent was washed with brine anddried over Na₂SO₄. The solvent was evaporated, and the residue waspurified on a silica gel column (PE/EA=10:1 to 1:1) to afford compound7-10 (1.1 g, crude).

Step 10. Compound (6)—

Compound 7-10 (1.1 g, 2.2 mmol) was dissolved in 100 mL of methanolicammonia, and the mixture was stirred at R.T. for 14 hours. The solventwas removed, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to give (6) as white solids (400 mg, 63%). ¹HNMR (CD₃OD, 400 MHz) δ 7.95 (d, J=8.8 Hz, 1H), 6.37 (d, J=6.0 Hz, 1H),5.70 (d, J=7.6 Hz, 1H), 4.04 (d, J=10.0 Hz, 1H), 3.83-3.92 (m, 2H),2.66-2.76 (m, 1H), 0.98 (d, J=6.8 Hz, 3H); ESI-MS: m/z=282.09 [M−H]⁻.

Example 7 Preparation of 4′-azidocytidine (7)

Step 1. Compound 4-2—

To a stirred solution of compound (8) (9.8 g, 34.4 mmol) in anhydrouspyridine (150 mL) was added BzCl (15.47 g, 110.08 mmol) dropwise at 0°C. The mixture was then stirred at R.T. for 14 hours. The reaction wasquenched with H₂O, and the solution was concentrated. The residue wasdissolved in EA and washed with saturated NaHCO₃. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified on a silicagel column (PE/EA=3:1) to give compound 4-2 (19.1 g, 93%).

Step 2. Compound 4-3—

Compound 4-2 (6.12 g, 10 mmol), 4-dimethylaminopyridine (DMAP) (1.22 g,10 mmol), TPSCl (6.04 g, 20 mmol) and Et₃N (5.05 g, 50 mmol) weresuspended in 100 mL of MeCN. The mixture was stirred at R.T. for 14hours. To the mixture was added NH₃ in THF (100 ml). The mixture stirredat R.T. for 2 hours. The solvent was removed, and the residue waspurified by column (DCM/MeOH=100:1 to 50:1) to give crude product (8.1g). The crude produce was dissolved in pyridine and BzCl (2.05 g, 14.6mmol) was added. The mixture was stirred at R.T for 16 hours andquenched with water. The solvent was removed, and the residue waspurified on a silica gel column to give compound 4-3 as a white foam(4.3 g, 61%).

Step 3. Compound (7)—

Compound 4-3 (4.3 g, 7.2 mmol) was dissolved in 100 mL of saturatedmethanolic ammonia, and the mixture was stirred at R.T. for 14 hours.The solvent was removed, and the residue was dissolved in H₂O and washedwith DCM. The aqueous phase was lyophilized and further purified byprep. HPLC (formic acid in water/methanol) to give (7) as a white solid(1.31 g, 64%). ¹H NMR (CD₃OD, 400 MHz) δ 7.95 (d, J=8 Hz, 1H), 6.13 (d,J=4.8 Hz, 1H), 5.92 (d, J=7.2 Hz, 1H), 4.29-4.35 (m, 2H), 3.66 (dd,J₁=35.2 Hz, J₂=12 Hz, 2H); ESI-MS: m/z=307.07 [M+Na]⁺.

Example 8 Preparation of 4′-azidouridine (8)

Step 1. Compound 3-2—

To a stirred suspension of compound 3-1 (30.5 g, 125 mmol), PPh₃ (39.3g, 150 mmol) and pyridine (100 mL) in anhydrous THF (200 mL) was addeddropwise a solution of I₂ (38.1 g, 150 mmol) in THF (100 mL) at 0° C.The mixture was warmed to R.T. and stirred for 14 hours. The precipitatewas removed by filtration, and the filtrate was concentrated. Theresidue was dissolved in EA and washed with saturated Na₂S₂O₃ aqueoussolution and then brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified on a silica gel column(DCM/MeOH=100:1 to 20:1) to afford compound 3-2 as a white solid (36.5g, 83%).

Step 2. Compound 3-3—

To a stirred solution of compound 3-2 (36.5 g, 103 mmol) in anhydrousMeOH (400 mL) was added NaOMe. The resulting solution was refluxed for16 hours at 80° C. The reaction was quenched with CO₂ (gas). Theprecipitate was removed by filtration, and the filtrate wasconcentrated. The residue was dissolved in THF and washed with brine anddried over Na₂SO₄. The solvent was removed, and the residue was purifiedon a silica gel column (MeOH/DCM=1/100 to 1/10) to afford compound 3-3as a white solid (21.4 g, 93%).

Step 3. Compound 3-4—

To a stirred solution of BnEt₃NCl (88.3 g, 379 mol) in MeCN (180 mL) wasadded NaN₃ (24.6 g, 379 mmol). The mixture was sonicated for 20 min andthen stirred at R.T. for 16 hours. The solution was filtrated into asolution of compound 3-3 (21.4 g, 94.7 mmol) and N-methylmorpholine(NMM) (7.8 g) in anhydrous THF (150 mL). The mixture was cooled to 0°C., and a solution of I₂ (96.3 g, 379 mmol) in THF (150 mL) was addeddropwise. Stirring was continued at R.T. for 14 hours. N-acetyl cysteinwas added until no gas evolved. Saturated Na₂S₂O₃ aqueous was addeduntil a light yellow solution achieved. The solution was concentratedand then diluted with EA. The organic phase was washed with brine anddried over Na₂SO₄. The solvent was removed, and the residue was purifiedon a silica gel column (DCM/MeOH=100/1 to 20/1) to give compound 3-4 asa white solid (31.8 g, 85%).

Step 4. Compound 3-5—

To a stirred solution of compound 3-4 (31.8 g, 80.5 mmol) in anhydrouspyridine (150 mL) was added BzCl (24.8 g, 177 mmol) dropwise at 0° C.The mixture was then stirred at R.T. for 14 hours. The reaction wasquenched with water, and the solution was concentrated. The residue wasdissolved in EA and washed with saturated NaHCO₃. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified on a silicagel column (PE/EA=10/1 to 1/1) to give compound 3-5 as a white foam(40.8 g, 84%).

Step 5. Compound (8)—

Compound 3-5 (40.8 g, 67.6 mmol), BzONa (97.3 g, 676 mmol) and15-crown-5 (148.7 g, 676 mmol) were suspended in 1000 mL of DMF. Themixture was stirred at 90-100° C. for 5 days. The precipitate wasremoved by filtration, and the filtrate was diluted with EA. The solventwas washed with brine and dried over Na₂SO₄. The solvent was removed,and the residue was purified on a silica gel column (PE/EA=10/1 to 1/1)to afford crude compound (23.8. g), which was further treated withmethanolic ammonia and purified on a silica gel column to give (8) as awhite solid (8.6 g, 45% for 2 steps). ¹H NMR (CD₃OD, 400 MHz) δ7.90 (d,J=8.0 Hz, 1H), 6.15 (d, J=5.6 Hz, 1H), 5.70 (t, J₁=7.6 Hz, J₂=0.4 Hz,1H), 4.36 (t, J=5.6 Hz, 1H), 4.27 (d, J=5.6 Hz, 1H), 3.63 (d, J=11.6 Hz,1H), 3.55 (d, J=12 Hz, 1H). ESI-TOF-MS: m/z=286 [M+H]⁺.

Example 9 Preparation of 4′-azido-2′-deoxy-2′-methylarabinocytidine (9)

Step 1. Compound 8-2—

Compound 8-2 (210 mg, 0.43 mmol), DMAP (52.5 mg, 0.43 mmol), TPSCl(259.72 mg, 0.86 mmol) and Et₃N (219 mg, 2.15 mmol) were suspended inMeCN (20 mL). The mixture was stirred at R.T. for 14 hours. To themixture was added THF.NH₃ (30 mL), and mixture was then stirred at R.T.for 2 hours. The solvent was removed and the residue was purified on asilica gel column (DCM/MeOH=100:1 to 50:1) to give compound 8-2 (100 mg,47.6%).

Step 2. Compound (9)—

Compound 8-2 (100 mg, 0.20 mmol) was dissolved in 50 mL of methanolicammonia, and the mixture was stirred at R.T. for 14 hours. The solventwas removed, and the residue was purified on a silica gel column(DCM/MeOH=20:1 to 10:1) to give (9) as a white solid (21.6 mg, 37.5%).¹H NMR (CD₃OD, 400 MHz) δ 8.01 (d, J=6.8 Hz, 1H), 6.42 (br s, 1H), 5.92(d, J=7.2 Hz, 1H), 3.99 (d, J=10.8 Hz, 1H), 3.87 (dd, J₁=12.0 Hz,J₂=26.8 Hz, 2H), 2.65-2.73 (m, 1H), 0.93 (d, J=6.8 Hz, 3H); ESI-TOF-MS:m/z=565.2 [2M+H]⁺.

Example 10 Preparation of 4′-azidoguanosine (10)

Step 1. Compound 52-2—

A solution of compound 52-1 (300 mg, 0.5 mmol), N²-acetylguanine (193mg, 1.0 mmol) and bis(trimethylsilyl)acetamide (BSA) (0.49 mL, 2.0 mmol)in 1,2-dichloroethane (5 mL) was stirred under reflux for 1.5 hours andcooled to R.T. TMSOTf (0.27 mL, 1.5 mmol) was added dropwise, and theresulting mixture was refluxed overnight. Additional N²-acetylguanine(193 mg), BSA (0.49 mL) and TMSOTf (0.27 mL) were added, and theresulting mixture was refluxed for 5 more days. After cooling to R.T.,the mixture was poured into NaHCO₃ solution in ice-water, passed througha celite pad, and washed with MeOH/DCM. The filtrate was passed anothercelite pad. Chromatography on silica gel with 2-10% MeOH in DCM gave 90mg of compound 52-2 and 39 mg of 53-1, both as solids.

Step 2. Compound (10)—

A solution of compound 52-2 (230 mg) in 7 M ammonia in methanol (30 mL)stood at R.T. overnight. The solvent was evaporated, and the residue wastriturated with MeOH, filtered, washed thoroughly with methanol to (10)(90 mg) as an off-white solid; ¹H NMR (DMSO-d₆) δ 3.49 (ABX, J=6.0 Hz,2H), 4.31 (m, 1H), 4.62 (m, 1H), 5.55 (t, J=6.0 Hz, 1H), 5.66 (d, J=6.0Hz, 1H), 5.75 (d, J=4.8 Hz, 1H), 5.97 (d, J=6.4 Hz, 1H), 6.53 (s, 2H),7.94 (s, 1H), 9.9 (br, 1H); MS: m/z=298.7 [M+H]⁺.

Example 11 Preparation of 4′-azidoarabinocytidine (11)

Step 1. Compound 6-2—

To a stirred solution of compound 12 (4.6 g, 16.2 mmol) in anhydrouspyridine (40 mL) was added BzCl (7.3 g, 51.8 mmol) dropwise at 0° C. Themixture was stirred at R.T. for 14 hours. The reaction was quenched withH₂O and the solution was concentrated. The residue was dissolved in EAand washed with saturated NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(PE/EA=10/1 to 1/1) to give compound 6-2 (7.4 g, 84.1%).

Step 2. Compound 6-3—

Compound 6-2 (7.4 g, 12.4 mmol), DMAP (3.1 g, 24.8 mmol), TPSCl (7.5 g,24.8 mol) and Et₃N (2.5 g, 24.8 mmol) were suspended in MeCN (50 mL).The mixture was stirred at R.T. for 14 hours. The solvent was removed,and the residue was dissolved in NH₃ (200 mL) in THF. The mixture wasstirred at R.T. for 2 hours. The solvent was removed, and the residuewas purified on a silica gel column (DCM/MeOH=100:1 to 50:1) to give thecrude product. The crude product was dissolved in anhydrous pyridine (50mL), and BzCl (1.7 g, 12.2 mmol) was added dropwise at 0° C. The mixturewas stirred at R.T. for 14 hours. The reaction was quenched with H₂O,and the solution was concentrated. The residue was dissolved in EA andwashed with saturated NaHCO₃. The organic layer was dried over Na₂SO₄and concentrated. The residue was purified on a silica gel column(PE/EA=10/1 to 1/1) to give compound 6-3 as a white foam (4.2 g, 48.4%).

Step 3. Compound (11)—

Compound 6-3 (4.2 g, 6.0 mmol) was dissolved in 200 mL of saturatedmethanolic ammonia, and the mixture was stirred at R.T. for 14 hours.The solvent was removed and then water added. The aqueous mixture waswashed with DCM several times and lyophilized to give (11) as a whitesolid (1.5 g, 88%). ¹H NMR (CD₃OD, 400 MHz) δ 7.74 (d, J=7.2 Hz, 1H),6.43 (d, J=5.6 Hz, 1H), 5.87 (d, J=7.6 Hz, 1H), 4.39 (dd, J₁=2.4 Hz,J₂=5.6 Hz, 1H), 4.15 (d, J=5.6 Hz, 1H), 3.80 (s, 1H). ESI-MS: m/z=285[M+H]⁺.

Example 12 Preparation of 4′-azidoarabinouridine (12)

Step 1. Compound 5-2—

A mixture of compound (8) (8.4 g, 29.6 mmol), diphenyl carbonate (7.7 g,35.5 mmol), sodium hydrogen carbonate (0.25 g, 2.96 mmol) in DMF (10 mL)was heated at 100° C. under N₂. After 14 h, the reaction mixture wascooled to R.T., and the solvent was removed under reduced pressure. Theresidue was suspended in MeOH, and the resulting precipitate wascollected by filtration to give compound 5-2 as a white solid (6.8 g,86%). ¹H NMR (DMSO-d6, 400 MHz) δ 7.91 (d, J=7.6 Hz, 1H), 6.58 (d, J=5.6Hz, 1H), 6.42 (d, J=6.4 Hz, 1H), 5.83 (dd, J₁=3.6 Hz, J₂=7.6 Hz, 1H),5.51 (t, J₁=6.0 Hz, J₂=5.6 Hz, 1H), 5.32 (dd, J₁=2.8 Hz, J₂=2.4 Hz, 1H),5.51 (dd, J₁=2.4 Hz, J₂=2.4 Hz, 1H), 3.38-3.49 (m, 2H).

Step 2. Compound (12)—

A solution of 5-2 (4.8 g, 18.0 mmol) and KOH (0.5 g, 9 mmol) in 9:1mixture of EtOH/H₂O (10 mL) was stirred at R.T. overnight. The solutionwas quenched with HCl. The solvent was removed, and the residue waspurified on a silica gel column (DCM/MeOH=50:1 to 10:1) to give (12)(4.6 g, 90.0%) as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ7.74 (d, J=8.0Hz, 1H), 6.36 (d, J=6.0 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H), 4.39 (t, J=6.0Hz, 1H), 4.18 (d, J=6.0 Hz, 1H), 3.82 (s, 2H); ESI-TOF-MS: m/z=286[M+H]⁺.

Example 13 Preparation of 4′-azido-2′-C-methylcytidine (13)

Compound (13) was prepared using the procedure set forth in the Journalof Medicinal Chemistry (2009) 52:219-224, which are hereby incorporatedby reference for the limited purpose of disclosing the procedure ofpreparing (13).

Example 14 Preparation of 4′-azido-2′-deoxy-2′-beta-fluorocytidine (14)

4′-azido-2′-deoxy-2′-beta-fluorocytidine was synthesized according to aprocedure set forth in The Journal Of Biological Chemistry (2008)283:2167-2175 and the Journal of Medicinal Chemistry (2009)52:2971-2978, which are hereby incorporated by reference for the limitedpurpose of disclosing the procedure of preparing (14).

Example 15 Preparation of 4′-azidouridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)eth-1-yl)thiophosphoramidate(15)

A solution of 4′-azidouridine (76 mg) and(O-phenyl-N—(S)-1-(isopropoxycarbonyl)eth-1-yl)thiophosphoramidicchloride (220 mg) in 2 mL of acetonitrile was treated withN-methylimidazole (0.2 mL), and the mixture was stirred at ambienttemperature under an argon atmosphere for 1 day. The mixture was dilutedwith ethyl acetate and washed successively with saturated aqueousammonium chloride, water, and brine. After drying the organic layerusing sodium sulfate, the solution was filtered and solvent removedunder reduced pressure. Following column chromatography using a gradientof 2-12% methanol in dichloromethane, it was noted that there wassignificant N-methylimidazole present in the crude product. The crudeproduct was dissolved in ethyl acetate and washed several times with 10%aqueous citric acid. The organic layer was dried and filtered asdescribed previously, the solvent was removed and another chromatographywas performed. The product (15) (12 mg) was obtained as an off-whitepowder (³¹P NMR (CDCl₃) δ 66.9, 67.8. LCMS: m/z=599.4 [M−H]⁺).

Example 16 Preparation of 4′-azidouridine5′-(O-phenyl-N—(S)-neopentoxycarbonyleth-1-yl)thiophosphoramidate (16)

A solution of 4′-azidouridine (140 mg) and(O-phenyl-N—(S)-1-(neopentylcarbonyl)eth-1-yl)thiophosphoramidicchloride (410 mg) in 5 mL of acetonitrile was treated withN-methylimidazole (0.5 mL), and the mixture was stirred at ambienttemperature under an argon atmosphere for 2 days. The mixture wasdiluted with ethyl acetate and washed successively with saturatedaqueous ammonium chloride, water, 10% aqueous citric acid and brine.After drying the organic layer using sodium sulfate, the solution wasfiltered, and solvent removed under reduced pressure. Following twocolumn chromatographies using a gradient of 3-12% methanol indichloromethane and 2-12% methanol in dichloromethane, the resultantcrude product was subjected to a final purification using HPLC. Theproduct (16) (13.5 mg) was obtained as an off-white powder (³¹P NMR(CDCl₃) 567.1, 68.1. LCMS: m/z=597.5 [M−H]⁺).

Example 17 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine (17)

Step 1. Compound 11-2—

To a stirred suspension of compound 11-1 (10.0 g, 40.6 mmol), PPh₃ (20.3g, 76.4 mmol) and pyridine (40 mL) in anhydrous THF (50 mL) was addeddropwise a solution of I₂ (24.0 g, 94.8 mmol) in THF (50 mL) at 0° C.After addition, the mixture was warmed to R.T. and stirred for 16 hours.The precipitate was removed by filtration, and the filtrate wasconcentrated. The residue was dissolved in EA and washed with saturatedaqueous Na₂S₂O₃ and then brine. The organic layer was dried over Na₂SO₄and concentrated. The residue was purified on a silica gel column(DCM/MeOH=100:1 to 50:1) to afford compound 11-2 (8.6 g, 59.3%) as awhite solid. ¹H NMR (CD3OD, 400 M Hz) δ 7.70 (d, J=8.0 Hz, 1H), 5.88(dd, J₁=1.6 Hz, J₂=20.8, 1H), 5.71 (d, J=8.4 Hz, 1H), 5.24 (dd, J₁=2.0Hz, J₂=5.2 Hz, 1H), 5.10 (dd, J₁=2.0 Hz, J₂=5.2 Hz 1H), 3.78-3.83 (m,1H), 3.61-3.65 (m, 1H), 3.44 (dd, J₁=J₂=6.0 Hz, 1H).

Step 2. Compound 11-3—

To a stirred solution of compound 11-2 (8.6 g, 24.2 mmol) in anhydrousDMF (40 mL) was added dropwise a solution of t-BuOK (6.3 g, 55.7 mmol)in DMF (40 mL) at 0° C. over 20 min. Stirring was continued for 20 minat 0° C. The mixture was quenched with aqueous NH₄Cl, diluted with EA,washed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (MeOH/DCM=1/100 to 1/50)to compound 11-3 as a white solid (4.2 g, 76.4%). ¹H NMR (CD3OD, 400 MHz) δ 7.51 (d, J=8.0 Hz, 1H), 6.05 (dd, J₁=1.2 Hz, J₂=17.2 Hz, 1H), 5.73(d, J=8.0 Hz, 1H), 5.26 (dd, J₁=1.2 Hz, J₂=4.8 Hz, 1H), 5.13 (dd, J₁=1.2Hz, J₂=4.8 Hz, 1H), 4.63 (dd, J₁=2.0 Hz, J₂=3.2 Hz, 1H), 4.41 (t, J₁=2.0Hz, J₂=2.0 Hz, 1H).

Step 3. Compound 11-4—

To a stirred solution of BnEt₃NCl (20.2 g, 86.3 mol) in MeCN (200 mL)was added NaN₃ (5.8 g, 69.2 mol). The mixture was sonicated for 20 minand then stirred at R.T. for 16 hours. The solution was filtrated into asolution of compound 11-3 (4.6 g, 27.2 mmol) and NMM (1.2 g) inanhydrous THF (60 mL). The mixture was cooled to 0° C., and a solutionof I₂ (24.0 g, 94.5 mol) in THF (40 mL) was added dropwise. Stirring wascontinued for 16 hours. N-Acetyl cystein was added until no gas evolved.The saturated aqueous Na₂S₂O₃ was added until a light yellow solutionachieved. The solution was concentrated and then diluted with EA. Theorganic phase was washed with brine and dried over Na₂SO₄. The solventwas removed, and the residue was purified on a silica gel column(DCM/MeOH=200/1 to 50/1) to give compound 11-4 (6.8 g, 85%).

Step 4. Compound 11-5—

To a stirred solution of compound 11-4 (6.8 g, 17.2 mmol) in anhydrouspyridine (50 mL) was added dropwise BzCl (2.9 g, 20.6 mmol) at 0° C. Themixture was then stirred at R.T. for 4 hours. The reaction was quenchedwith H₂O, and the solution was concentrated. The residue was dissolvedin EA and washed with saturated aqueous NaHCO₃. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified on a silicagel column (PE/EA=10/1 to 1/1) to give compound 11-5 (7.4 g, 86%) as awhite foam.

Step 5. Compound 11-6—

Compound 11-5 (7.4 g, 14.9 mmol), BzONa (21.5 g, 149 mmol) and15-crown-5 (32.8 g, 149 mmol) were suspended in DMF (400 mL). Themixture was stirred at 70-80° C. for 5 days. The precipitate was removedby filtration, and the filtrate was diluted with EA. The solvent waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (PE/EA=10/1 to 1/1) toafford compound 11-6 (2.4 g, crude).

Step 6. Compound (17)—

Compound 11-6 (2.4 g, 4.8 mmol) was dissolved in methanolic ammonia (40mL), and the mixture was stirred at R.T. for 14 hours. The solvent wasremoved, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to give (17) as a white solid (150 mg). ¹H NMR(CD₃OD, 400 M Hz) δ 7.83 (d, J=8.4 Hz, 1H), 6.15 (dd, J₁=2.0 Hz, J₂=15.2Hz, 1H), 5.70 (d, J=8.0 Hz, 1H), 5.27 (dd, J₁=1.2 Hz, J₂=5.2 Hz, 1H),514 (dd, J₁=1.2 Hz, J₂=5.2 Hz, 1H), 4.57 (dd, J₁=5.6 Hz, J₂=10.8 Hz,1H), 3.81 (d, J=12.0 Hz, 1H), 3.71 (d, J=12.0 Hz, 1H); ESI-MS: m/z=287[M+H]⁺.

Example 18 Preparation of 4′-azido-2′-deoxy-2′,2′-difluorocytidine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (18)

To a stirred mixture of compound (1) (61 mg, 0.2 mmol) in anhydrous THF(5 mL) was added a solution of t-BuMgCl (0.44 mL, 1M in THF) dropwise at−78° C. The mixture was then stirred at 0° C. for 30 min and re-cooledto −78° C. A solution ofO-phenyl-N—(S)-1-(isopropoxycarbonyl)ethylphosphoramidic chloride (122mg, 0.4 mmol) in THF (1 mL) was added dropwise. After addition, themixture was stirred at 25° C. for 16 hours. The reaction was quenchedwith HCOOH (80% aq.) at 0° C. The solvent was removed, and the residuewas purified on a silica gel column (DCM:MeOH=50:1 to 10:1) to give (18)as a white solid (25 mg, 22%). ¹H NMR (DMSO-d₆, 400 MHz) δ7.52-7.56 (m,3H), 7.34-7.40 (m, 2H), 7.18-7.24 (m, 3H), 6.94 (br s, 1H), 6.31 (br s,1H), 6.19 (dd, J₁=10 Hz, J₂=10.8 Hz, 1H), 5.77 (d, J=7.6 Hz, 1H),4.81-4.87 (m, 1H), 4.66 (br s, 1H), 4.36-4.46 (m, 2H), 3.77-3.84 (m,1H), 1.21 (d, J=7.2 Hz, 3H), 1.13 (d, J=2.4 Hz, 3H), 1.21 (d, J=2.8 Hz,3H). ³¹P NMR (DMSO-d₆, 162 MHz) δ3.49. ESI-LCMS: m/z=574.1 [M+H]⁺.

Example 19 Preparation of 4′-azido-2′-deoxy-2′,2′-difluorouridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (19)

Compound 19 (white solid, 29 mg, 25%) was prepared using the procedurefor preparing compound 18 with (compound (2), 61 mg, 0.2 mmol) in placeof compound (1). ¹H NMR (CD₃OD, 400 MHz) δ7.43 (d, J=8.0 Hz, 1H),7.27-7.31 (m, 2H), 7.10-7.19 (m, 3H), 6.22 (t, J=7.2 Hz, 1H), 6.10 (d,J=8.0 Hz, 1H), 4.86-4.90 (m, 1H), 4.31-4.47 (m, 3H), 4.80-4.86 (m, 1H),1.25 (d, J=7.2 Hz, 3H), 1.14-1.14 (m, 6H). ³¹P NMR (CD₃OD, 162 MHz)δ1.97, 1.86. ESI-LCMS: m/z=575 [M+H]⁺.

Example 20 Preparation of 4′-azido-2′-deoxy-2′-fluoroarabinouridine (20)

Step 1. Compound 9-2—

To a stirred suspension of compound 9-1 (9.0 g, 36.6 mmol), imidazole(15.9 g, 234.0 mmol), PPh₃ (17.96 g, 68.58 mmol) and pyridine (90 mL) inanhydrous THF (360 mL) was added dropwise a solution of I₂ (21.67 g,85.32 mmol) in THF (350 mL) at 0° C. After addition, the mixture waswarmed to R.T. and stirred for 14 hours. The solution was quenched withsaturated aqueous Na₂S₂O₃ (150 mL) and extracted with EA (100 mL, 3times). The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified on a silica gel column (DCM/MeOH=100:1 to 10:1) toafford compound 9-2 (7.1 g, 54%) as a white solid.

Step 2. Compound 9-3—

To a stirred solution of compound 9-2 (0.7 g, 1.966 mmol) in anhydrousDMF (20 mL) was added dropwise a suspension of t-BuOK (0.660 g, 5.898mmol) in DMF (10 mL) at 0° C. over 10 min. The mixture was stirred atR.T. for 2 hrs. The mixture was then quenched with saturated aqueousNH₄Cl (10 mL), and extracted with THF and EA. The organic layer waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (MeOH/DCM=1/100 to 1/30)to afford compound 9-3 as a white solid (0.4 g, 89.2%).

Step 3. Compound 9-4—

To a stirred solution of BnEt₃NCl (17.0 g, 73 mmol) in MeCN (73 mL) wasadded NaN₃ (4.74 g, 73 mmol). The mixture was sonicated for 20 min andthen stirred at R.T. for 16 hours. The solution was filtrated into asolution of compound 9-3 (3.33 g, 14.6 mmol) and NMM (7.37 g, 73 mmol)in anhydrous THF (100 mL). The mixture was cooled to 0° C. A solution ofI₂ (18.54 g, 73 mmol) in THF (50 mL) was added dropwise. Stirring wascontinued at 0-10° C. for 20 hours. N-acetyl cystein was added until nogas evolved. Saturated aqueous Na₂S₂O₃ was added until a light yellowsolution achieved. The solution was concentrated and then diluted withEA. The organic phase was washed with brine and dried over Na₂SO₄. Thesolvent was removed, and the residue was purified by column(PE:EA:DCM=1:1:1) to give compound 9-4 (3.9 g, 67.2%) as a white solid.¹H NMR (CD₃OD, 400 MHz) δ11.59 (br s, 1H), 7.60 (dd, J₁=8.4 Hz, J₂=2.0Hz, 1H), 6.90 (d, J=5.6 Hz, 1H), 6.35 (dd, J₁=14 Hz, J₂=5.2 Hz, 1H),5.71 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H), 5.32 (dt, J₁=53.6 Hz, J₂=4.8 Hz,1H), 4.65 (dt, J₁=21.6 Hz, J₂=4.2 Hz, 1H), 3.73 (dd, J₁=19.2 Hz, J₂=11.6Hz, 2H).

Step 4. Compound 9-5—

To a stirred solution of compound 9-4 (1.0 g, 2.51 mmol) in anhydrouspyridine (20 mL) was added BzCl (0.528 g, 3.77 mmol) dropwise at 0° C.The mixture was stirred at R.T. for 10 hours. The reaction was quenchedwith H₂O, and the solution was concentrated. The residue was dissolvedin EA and washed with saturated NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(PE/EA=10/1 to 1/1) to give compound 9-5 (0.9 g, 72.1%) as a white foam.

Step 5. Compound 9-6—

Compound 9-5 (0.85 g, 1.69 mmol), BzONa (2.44 g, 16.9 mmol) and15-crown-5 (3.71 g, 16.9 mmol) were suspended in DMF (80 mL). Themixture was stirred at 60-70° C. for 3 days. The precipitate was removedby filtration, and the filtrate was diluted with EA. The solution waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (PE/EA=4/1 to 2/1) toafford compound 9-6 (0.6 g, 59.4%) as a light yellow foam.

Step 6. Compound (20)—

Compound 9-6 (0.6 g, 1.02 mmol) was dissolved in saturated methanolicammonia (30 mL), and the mixture was stirred at R.T. for 14 hours. Thesolvent was removed, and the residue was purified by column(DCM/MeOH=30:1 to 10:1) to give (20) as a white solid (0.1 g, 34.8%). ¹HNMR (CD₃OD, 400 MHz) δ 7.75 (dd, J₁=8.0 Hz, J₂=1.2 Hz, 1H), 6.46 (dd,J₁=11.2 Hz, J₂=5.2 Hz, 1H,), 5.72 (d, J=8.4 Hz, 1H), 5.21 (dt, J₁=13.6Hz, J₂=5.2 Hz, 1H), 4.51 (dd, J₁=22 Hz, J₂=4.8 Hz, 1H); ESI-MS: m/z=288[M+H]⁺.

Example 21 Preparation of 4′-azidouridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)eth-1-yl)phosphoramidate (21)

Step 1. Compound of 19-2—

A mixture of compound (8) (650 mg, 2.3 mmol), trimethyl orthoformate(5.0 mL) and p-toluenesulfonic acid monohydrate (0.73 g, 6.9 mmol) in1,4-dioxane (10 mL) was stirred at R.T. for 24 hours, cooled with ice,quenched by triethylamine (2 mL) and concentrated. The residue waspurified by HPLC to give compound 19-2 as a white foam (168 mg, 22.7%).

Step 2. Compound of 19-3—

To a solution of compound 19-2 (186 mg, 0.6 mmol) in THF (10 mL) underargon was added 1.0 M t-BuMgBr in THF (3.0 mL, 3.0 mmol) at 0° C. Theresulting solution was stirred at R.T. for 30 min andO-phenyl-N—(S)-1-(isopropoxycarbonyl)ethylphosphoramidic chloride (3 mL,1M in THF) was added at 0° C. The reaction mixture was stirred at R.T.for 20 hours and quenched with water at 0° C. The solution was dilutedwith EA, washed with brine, and dried over MgSO₄. After concentration,the residue was purified on silica gel (PE:EA=2:1 to 1:1) to givecompound 19-3 (192 mg, 58%) as a white foam.

Step 3. Compound (21)—

Compound 19-3 (192 mg, 0.35 mmol) was dissolved in 80% formic acid (20mL) and stirred at R.T. overnight. The solvent was then evaporated atR.T. The residue was purified by chromatography on silica gel with10-15% MeOH in DCM, followed by reverse-phase HPLC with MeCN/water togive (21) as a white solid (a mixture of 2 P-isomers, 92 mg, 52%). ¹HNMR (CD₃OD, 400 MHz) δ 7.64 (d, J=8.0 Hz, 1H), 7.33-7.38 (m, 2H),7.17-7.25 (3H), 6.14 (d, J=5.6 Hz, 1H), 5.69 (d, J=8.0 Hz, 1H),4.93-4.98 (m, 1H), 4.951 (m, 1H), 4.29-4.36 (m, 2H), 4.09-4.21 (m, 1H),3.88-3.92 (m, 1H), 1.28-1.31 (m, 3H), 1.19-1.23 (m, 6H); ³¹P NMR (CD₃OD,162 MHz) δ 3.32, 3.26; ESI-MS: m/z=555 [M+H]⁺.

Example 22 Preparation of 4′-azidocytidine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (22)

To a stirred solution of compound (7) (150 mg, 0.53 mmol) in dry THF (15mL) was added t-BuMgCl (1M in THF, 1.33 mmol) dropwise at −78° C. Thesolution was then warmed to R.T., and the mixture was stirred for 20min. The mixture was cooled to −78° C. and(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidic chloride (1Min THF, 1.06 mmol) was added. The mixture was warmed to R.T. graduallyand stirred for 3 hours. The reaction was quenched by HCOOH andconcentrated. The residue was purified by prep. HPLC to give (22) as awhite solid (22.7 mg, 7.9%). ¹H NMR (DMSO-d6, 400 MHz) δ 7.58-7.60 (m,1H), 7.53 (br s, 1H), 7.44 (br s, 1H), 7.33-7.38 (m, 2H), 7.15-7.22 (m,3H), 6.07-6.16 (m, 2H), 5.88-5.90 (m, 1H), 5.71-5.75 (m, 1H), 5.59-5.61(m, 1H), 4.80-4.89 (m, 1H), 4.17-4.26 (m, 2H), 4.07-4.12 (m, 1H),3.92-4.05 (m, 1H), 3.72-3.82 (m, 1H), 1.18-1.21 (m, 3H), 1.12-1.15 (m,6H); ³¹P NMR (DMSO-d6, 162 MHz) δ 3.46, 3.41; ESI-MS: m/z=553 [M+H]⁺.

Example 23 Preparation of 4′-azido-2′-deoxy-2′-fluorocytidine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (23)

Compound 23 (white solid, 16.2 mg, 5.8%) was prepared using theprocedure for preparing compound 22 with (compound (2), 150 mg, 0.52mmol) in place of compound (7). ¹H NMR (DMSO-d6, 400 MHz) δ 7.65-7.67(m, 1H), 7.57 (br s, 1H), 7.48 (br s, 1H), 7.32-7.37 (m, 2H), 7.16-7.22(m, 3H), 6.00-6.19 (m, 3H), 5.72-5.76 (m, 1H), 5.29-5.30 (m, 1H),5.16-5.18 (m, 1H), 4.77-4.86 (m, 1H), 4.56-4.66 (m, 2H), 4.11-4.31 (m,2H), 3.71-4.83 (m, 1H), 1.19-1.21 (m, 3H), 1.12-1.15 (m, 6H); ³¹P NMR(DMSO-d6, 162 MHz) δ 3.44; ESI-MS: m/z 555 [M+H]⁺.

Example 24 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (24)

To a stirred solution of compound (17) (50 mg, 0.17 mmol) in anhydrousTHF (20 mL) was added a solution of t-BuMgCl (0.35 mL, 1M in THF)dropwise at −78° C. The mixture was then stirred at R.T. for 40 min andcooled to −78° C. A solution of0-phenyl-N—(S)-1-(isopropoxycarbonyl)ethylphosphoramidic chloride (106mg, 0.35 mmol) was added dropwise. After addition, the mixture wasstirred at R.T. for 18 hours. The reaction was quenched with HCOOH.After concentration, the residue was purified by prep. HPLC to give (24)(11.96 mg, 12.3%) as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ7.62 (d,J=7.2 Hz, 1H), 7.15-7.62 (m, 5H), 6.03 (d, J=16.4 Hz, 1H), 5.63 (d,J=8.0 Hz, 1H), 5.28 (dd, J₁=5.6 Hz, J₂=54 Hz, 1H), 4.91-4.95 (m, 1H),4.66 (dd, J₁=5.2 Hz, J₂=60 Hz, 1H), 4.21-4.35 (m, 2H), 3.88-3.92 (m,1H), 1.31 (d, J=7.2 Hz, 3H), 1.18-1.21 (m, 6H); ³¹P NMR (CD₃OD, 162 MHz)δ1.77; ESI-MS: m/z=557 [M+H]⁺.

Example 25 Preparation of2-amino-7-(4-azido-β-D-ribofuranos-1-yl)-1H-purin-6(7H)-one (25)

A solution of 53-1 (80 mg) in 7 M ammonia in methanol (15 mL) stood atR.T. overnight. The solvent was evaporated, and the residue wastriturated with MeOH, filtered, washed thoroughly with methanol to give(25) (41 mg) as an off-white solid; ¹H NMR (DMSO-d₆) δ 3.43 (q, J=6.0Hz, 1H), 3.60 (q, J=6.0 Hz, 1H), 4.30 (t, J=6.0 Hz, 1H), 4.60 (dd,J=6.4, 8.0 Hz, 1H), 5.48 (t, J=6.4 Hz, 1H), 5.59 (d, J=6.8 Hz, 1H), 6.21(s, 2H), 6.25 (d, J=6.4 Hz, 1H), 8.31 (s, 1H), 10.9 (br, 1H); MS: m/z298.7 (M+H)⁺.

Example 26 Preparation of 4′-azido-2′-deoxy-2′-fluorouarabinoridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (26)

To a stirred solution of 4′-azido-2′-deoxy-2′-fluorouarabinoridine (60mg, 0.21 mmol) in anhydrous THF (20 mL) was added a solution of t-BuMgCl(0.42 mL, 1M in THF) dropwise at −78° C. The mixture was then stirred atR.T. for 40 min and re-cooled to −78° C. A solution ofO-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidic chloride (127mg, 0.42 mmol) in THF was added dropwise. After addition, the mixturewas stirred at R.T. for 18 hours as checked with LCMS. Then the reactionwas quenched with HCOOH. After concentration, the residue was purifiedby prep. HPLC to give (23) (3.26 mg, 2.7%) as white solid. ¹H NMR(CD₃OD, 400 MHz) δ7.63 (d, J=7.2 Hz, 1H), 7.21-7.42 (m, 5H), 6.51 (dd,J₁=4.8 Hz, J₂=14.8 Hz, 1H), 5.68 (d, J=8.0 Hz, 1H), 5.15-5.30 (m, 1H),4.98-5.02 (m, 1H), 4.54 (dd, J₁=3.6 Hz, J₂=20 Hz, 1H), 4.31-4.43 (m,2H), 3.93-3.97 (m, 1H), 1.35-1.38 (m, 3H), 1.23-1.26 (m, 6H); ³¹P NMR(CD₃OD, 162 MHz) δ 3.50; ESI-LCMS: m/z 557 [M+H]⁺.

Example 27 Preparation of 4′-azido-2′-deoxy-2′-fluoroguanosine (27)

Step 1. Compound 50-2—

To an ice-cooled solution of commercial 2′-fluoro-2′-deoxyguanosine(50-1) (5.0 g, 17.54 mmol) in anhydrous DMF (150 mL) was added imidazole(3.0 g, 43.85 mmol) followed by TBDPSCl (5.8 ml, 21.05 mmol) under N₂.The reaction mixture was stirred at R.T. overnight. Resulting reactionmixture residue was diluted with EA (300 mL), washed with water andbrine. The organic layer was separated, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuum to a white solid,which was purified on silica gel column (CH₃OH:DCM; 9:1) to givecompound 50-2 (4.1 g, 45%).

Step 2. Compound 50-3—

MMTrCl (4.6 g, 15.06 mmol) was added into a solution of compound 50-2(3.94 g, 7.53 mmol) in anhydrous DMF (40 mL), DMAP (55.0 mg, 0.45 mmol).TEA (2.2 ml, 15.06 mmol) was added. The reaction mixture was stirred atR.T. overnight under N₂, until TLC showed the reaction was completed.The reaction mixture was diluted with EA (300 mL), washed with water andbrine. The organic layer was separated, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuum to give as residue,which was purified on silica gel column using DCM/MeOH (90:10) to givecompound 50-3 (5.2 g, 87%).

Step 3. Compound 50-4—

TEA.3HF (4.2 ml, 26.12 mmol), TEA (2.83 ml, 19.6 mmol), was addeddropwise into a solution compound 36-3 (5.2 g, 6.53 mmol) in anhydrousTHF (25 mL) and stirred at R.T. overnight until TLC showed the reactionwas complete. The reaction mixture was diluted with EA (200 mL), washedwith water and brine. The organic layer was separated, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuumto give as residue, which was purified on silica gel column usingDCM/MeOH (9:1) to give compound 50-4 (3.1 g, 85%).

Step 4. Compound 50-5—

To a mixture of compound 50-4 (3.5 g, 6.3 mmol), triphenylphosphine (3.3g, 12.6 mmol), and imidazole (855 mg, 12.6 mmol), was added anhydrousTHF (20 mL). The resulted clear solution was stirred for 5 min. To thesolution was slowly added I₂ (2.44 g, 9.45 mmol) in THF (4 ml). Thereaction mixture was stirred at R.T. for overnight. The reaction mixturewas cooled on an ice-water bath, diluted with EA (200 mL), washed with0.5 M aqueous Na₂S₂O₃ and brine. The organic layer was separated, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated invacuum to give as residue, which was purified on silica gel column usingDCM/MeOH (93:7 to 90:10) to give compound 50-5 (2.14 g, 51%).

Step 5. Compound 50-6—

To a solution of compound 50-5 (5.0 g, 17.54 mmol) in anhydrous THF (30mL) was added DBU (0.45 ml, 43.85 mmol), and reaction mixture wasstirred at 60° C. for overnight. The reaction mixture residue wasdiluted with EA (150 mL), and washed with water and brine. The organiclayer was separated, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuum to give as a white solid, which waspurified on silica gel column using DCM/MeOH (95:5) to compound 50-6(1.09 g, 82%).

Step 6. Compound 50-7—

Benzyltriethylammonium chloride (3.73 mmol, 850 mg) and sodium azide(3.85 mmol, 250 mg) were suspended in anhydrous CH₃CN (15 mL). Thesuspension was sonicated for 5 min and stirred vigorously for 3 hours.The mixture was filtered, and the filtrate containing quaternaryammonium azide was added to a solution of compound 50-6 (1.0 g, 1.86mmol,) and 4-methylmorpholine (0.64 mmol, 70 uL) in anhydrous THF (15mL). A solution of I₂ (3.12 mmol, 790 mg) in anhydrous THF (5 mL) wasadded dropwise over 1 hour under stirring at 0° C. The reaction mixturewas stirred at 0° C. for 30 min, and then 20 hours at R.T. to give a4′-azido intermediate. 4-methylmorpholine (8.5 mmol, 0.94 ml) and DMAP(0.26 g, 2.10 mmol) were added, followed by BzCl (5.55 mmol, 0.65 ml).The reaction mixture was stirred at 0 to 5° C. (ice/water bath) for 2hours at R.T. A solution of 0.1 M Na₂SO₃ in saturated aqueous NaHCO₃ (50mL) was added, and the mixture was shaken. The mixture was diluted withEA (250 mL), and washed with saturated aqueous NaHCO₃ and water. Theorganic layer was separated and the aqueous layer washed with saturatedaqueous NaCl solution, dried (Na₂SO₄), filtered, and evaporatedin-vacuo, and purified by silica gel (DCM/MeOH; 95:5) to give compound50-7 (1.27 g).

Step 7. Compound 50-8—

Compound 50-7 (894 mg, 1.1 mmol) was dissolved in DMF (20 mL), togetherwith 15-crown-5 (0.88 mL, 4.4 mmol) and sodium benzoate (635 mg, 4.44mmol). The resulting suspension was stirred for 16 hours at 110° C.Additional sodium benzoate (160 mg, 1.1 mmol) and 15-crown-5 (0.22 mL,1.1 mmol) were added, and the mixture was stirred for 1 day at 110° C.The resulted light brown suspension was filtered through celite, and thefiltrate evaporated to dryness under reduced pressure. The residue wastreated with EtOAc, and the mixture was washed with aqueous NaHCO₃,brine. The organic layer was separated, washed with water, dried(Na₂SO4), and evaporated to dryness under reduced pressure. Purificationby silica gel column chromatography provided compound 50-8 as anoff-white solid (580 mg, 65%).

Step 8. Compound (27)—

A solution of compound 50-8 (580 mg, 0.72 mmol) in 7N NH₃ in CH₃OH (30mL) was stirred at R.T. overnight. The solvent was evaporated in vacuo,and the residue was purified on silica gel column using DCM/MeOH (95:5to 90:10) to give4′-azido-2′-fluoro-N²-(4-methoxytrityl)-2′-deoxyguanosine (332 mg, 77%).4′-Azido-2′-fluoro-N²-(4-methoxytrityl)-2′-deoxyguanosine (80 mg, 0.13mmol) was dissolved in 80% HCOOH (3 mL), stirred at R.T. for 3 hours.The solvent was evaporated at R.T. and co-evaporated with MeOH/toluene(3 times). Purification using RP-HPLC (water:acetonitrile) gave (27)(26.0 mg, 61%) as a white foam after lyophilization. ¹H NMR (DMSO-d₆) δ3.55-3.67 (m, 2H), 4.69-4.77 (m, 1H), 5.37 (dd, J=2.4, 4.8 Hz, 1H), 5.51(t, J=2.8 Hz, 1H), 5.65 (t, J=6.0 Hz, 1H), 6.13 (d, J=7.6 Hz, 1H), 6.30(dd, J=2.4, 18.4 Hz, 1H), 6.60 (br s, 1H), 7.91 (s, 1H), 10.74 (br s,1H); ¹⁹F NMR δ (−199.0 to −199.25, m); ESI-LCMS m/z=325.3 [M+H]⁺.

Example 28 Preparation of 4′-azido-2′-deoxy-2′-fluoroadenosine (28)

Step 1. Compound 13-2—

To a stirred suspension of compound 13-1 (2.5 g, 9.3 mmol), PPh₃ (7.8 g,29.8 mmol) and pyridine (2 mL) in anhydrous THF (50 mL) was addeddropwise a solution of I₂ (7.6 g, 29.9 mmol) in THF (5 mL) at 0° C.After addition, the mixture was warmed to R.T. and stirred for 48 hours.The solution was quenched with MeOH (50 mL) and concentrated, and theresidue was purified on a silica gel column (DCM/MeOH=100:1 to 10:1) toafford compound 13-2 as a white solid (3.1 g, 87.9%). ¹H NMR (DMSO-d6,400 MHz) δ8.31 (s, 1H), 8.14 (s, 1H), 7.36 (br s, 2H), 6.23-6.22 (d,J=19.6 Hz, 1H), 5.93-5.95 (m, 1H), 5.57-5.69 (m, 1H), 4.48-4.54 (m, 1H),3.89-3.90 (m, 1H), 3.59-3.62 (m, 1H), 3.40-3.44 (m, 1H).

Step 2. Compound 13-3—

To a stirred solution of compound 13-2 (3.1 g, 8.2 mmol) in anhydrousTHF (50 mL) was added DBU (3.7 g, 24.0 mmol). The mixture was stirred at60° C. for 2 hours. The reaction mixture was concentrated, and theresidue was triturated with DCM to afford compound 13-3 as a white solid(1.6 g, 77.7%). ¹H NMR (DMSO-d6, 400 MHz) δ8.32 (s, 1H), 8.16 (s, 1H),7.42 (bs, 2H), 6.54 (d, J=18.0 Hz, 1H), 6.04-6.06 (m, 1H), 5.56-5.71 (m,1H), 4.42-4.51 (m, 1H), 4.44 (s, 1H), 4.26 (s, 1H).

Step 3. Compound 13-4—

To a stirred solution of BnEt₃NCl (17.0 g, 73 mmol) in MeCN (73 mL) wasadded NaN₃ (4.74 g, 73 mmol). The mixture was sonicated for 20 min andthen stirred at R.T. for 16 hours. The solution (56 mL) was filtratedinto a solution of compound 13-3 (1.8 g, 7.2 mmol) and NMM (4.5 g, 56.3mmol) in anhydrous THF (50 mL). The mixture was cooled to 0° C., and asolution of I₂ (14.2 g, 55.9 mmol) in THF (10 mL) was added dropwise.Stirring was continued at R.T. for 20 hours. N-Acetyl cystein was addeduntil no gas evolved. Saturated aqueous Na₂S₂O₃ was added until a lightyellow solution achieved. The solution was separated, and the waterlayer was extracted by EA (50 mL, 2 times). The combined organic layerwas dried and concentrated, and the residue was purified on a silica gelcolumn to give compound 13-4 (crude 3.9 g, >100%).

Step 4. Compound 13-5—

To a stirred solution of compound 13-4 (crude 3.9 g, 7.2 mmol) inanhydrous pyridine (30 mL) was added BzCl (5.88 g, 42 mmol) dropwise at0° C. The mixture was stirred at R.T. for 16 hours. The reaction wasquenched with H₂O, and the solution was concentrated. The residue wasdissolved in EA and washed with saturated aqueous NaHCO₃. The organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedon a silica gel column (PE/EA=10/1 to 1/1) to give compound 13-5 (2.1 g,39.8% for two step). ¹H NMR (CDCl₃, 400 MHz) δ8.73 (s, 1H), 8.25 (s,1H), 8.15-8.17 (m, 2H), 7.85-7.87 (m, 4H), 7.64-7.70 (m, 1H), 7.48-7.54(m, 4H), 7.36-7.40 (m, 4H), 6.44-6.49 (m, 1H), 6.29-6.36 (m, 1H),6.00-6.16 (m, 1H), 3.69-3.78 (m, 2H).

Step 5. Compound 13-6—

Compound 13-5 (1.5 g, 2.05 mmol), BzONa (2.9 g, 20.1 mmol) and15-crown-5 (4.4 g, 20.0 mmol) were suspended in DMF (80 mL). The mixturewas stirred at 105° C. for 16 hours. The precipitate was removed byfiltration, and the filtrate was diluted with EA. The solvent was washedwith brine and dried over Na₂SO₄. The solvent was removed, and theresidue was purified on a silica gel column (PE/EA=4/1 to 2/1) to affordcompound 13-6 (crude 1.3 g, 73%).

Step 6. Compound (28)—

Compound 13-6 (1.3 g, 2.1 mmol) was dissolved in methanolic ammonia (30mL), and the mixture was stirred at R.T. for 16 hours. The solvent wasremoved, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to (28) as a white solid (450 mg, 69.1%). ¹H NMR(CD₃OD, 400 MHz) δ 8.36 (s, 1H), 8.22 (s, 1H), 6.67 (dd, J₁=16.8 Hz,J₂=2.8 Hz, 1H), 5.56-5.71 (m, 1H), 4.96 (dd, J₁=20.8 Hz, J₂=5.4 Hz, 1H),3.85-3.79 (m, 2H); ESI-MS: m/z=310.9 [M+H]⁺.

Example 29 Preparation of 4′-azidoguanosine5′-[O-phenyl-N—((S)-cyclohexoxycarbonyleth-1-yl))phosphoramidate (29)

Step 1. Compound 54-1—

A mixture of compound 52 (293 mg, 0.9 mmol) and p-TSOH (257 mg, 1.35mmol), and trimethylorthoformate (5.4 mL) in 1,4-dioxane was stirred atR.T. overnight. Dowex MWA-1 basic resin was added and stirred for 3hours. The resin was filtered out and washed thoroughly with MeOH/DCM.Chromatography on silica gel with 7-12% MeOH in DCM gave compound 53-1(245 mg).

Step 2. Compound 54-2—

Tert-butylmagnesium bromide in THF (1.0 M, 0.29 mL) was added dropwiseto a stirred solution of compound 54-1 in anhydrous THF (0.8 mL). Theresulting solution was stirred at R.T. for 15 min.O-Phenyl-N—(S)-1-(cyclohexoxycarbonyl)ethylphosphoramidic chloride (0.29mL) was added dropwise during 5 min, and the resulting mixture wasstirred at R.T. overnight. The mixture was cooled with ice, quenchedwith TEA (0.1 mL) and aqueous NH₄Cl, diluted with ethyl acetate, washedwith aqueous NH₄Cl four times, washed with 5% NaHCO₃ two times, driedover Na₂SO₄, and concentrated. Chromatography on silica gel with 3-7%MeOH in DCM gave the crude compound 53-2 as an off-white solid.

Step 3. Compound (29)—

Compound 54-2 was dissolved in 4 mL of 80% formic acid and 20% water,and the resulting solution stood at R.T. for 5 hours. The solvent wasevaporated at 30° C. Chromatography on silica gel with 10-15% MeOH inDCM gave crude 53 (63 mg), which was further purified on RP HPLC withacetonitrile and water to give (29) (36 mg) as a white solid; ¹H NMR(CD₃OD, two P-isomers) δ 1.20-1.56 (m, 9H), 1.65-1.83 (m, 4H), 3.83-3.92(m, 1H), 4.29 (ABX, J=5.6 Hz, 1.6H), 4.30 (ABX, J=5.6 Hz, 0.4H), 4.59(d, J=5.6 Hz, 0.8H), 4.66-4.74 (m, 1H), 4.85 (t, J=5.6 Hz, 0.8H), 4.91(t, J=5.6 Hz, 0.2H), 6.07 (d, J=5.6 Hz, 0.2H), 6.10 (d, J=5.6 Hz, 0.8H),7.10-7.36 (m, 5H), 7.85 (s, 0.2H), 7.86 (s, 0.8H); MS: m/z=763.3 [M+H]⁺.

Example 30 Preparation of 4′-azido-2′-deoxy-2′,2′-difluoroguanosine (30)

Step 1. Compound 16-2—

To a stirred solution of compound 16-1 (100.0 g, 265.9 mmol) in dry THF(1000 mL) was added Li(O-t-Bu)₃AlH (318.9 mL, 318.9 mmol) at −78° C.under N₂. The mixture was stirred at −78° C. for 1 hour and then at R.T.for an additional 1 hour. The reaction mixture was cooled to −50° C. andquenched with ice and a saturated NH₄Cl solution. The resulting mixturewas extracted with EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated to afford the crude product (100.5 g) as a white solid,which was dissolved in dry DCM (600 mL). To the mixture was addeddropwise NEt₃ (110 mL) and MsCl (45.5 g, 298.0 mmol) at 0° C., and thereaction mixture was stirred at R.T. for 2 hour, quenched with ice waterat 0° C., and extracted with DCM. The organic layer was dried overNa₂SO₄, concentrated and purified on silica gel column to affordcompound 16-2 (113.4 g, yield 93.9%) as a white solid.

Step 2. Compound 16-3—

To a suspension of compound 6-chloro-9H-purin-2-amine (70.1 g, 414.7mmol), HMDS (480 mL) and (NH₄)₂SO₄ (0.8 g) was added dry DCE (400 mL).The mixture was refluxed under N₂ for 18 hours and then cooled to R.T.To the silylated 2-amino-6-chloropurine solution was added compound 16-2(78.0 g, 171.1 mmol) and TMSOTf (60 mL, 331.9 mmol). The reactionmixture was refluxed overnight and concentrated and neutralized with aNaHCO₃ solution. The resulting precipitate was filtered off, and thefiltrate was extracted with EtOAc. The organic layer was dried overNa₂SO₄ and concentrated. Purification on a silica gel column to givecompound 16-3 (10.8 g, yield 11.9%) as a light yellow solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.36 (s, 1H), 8.36-8.05 (m, 4H), 7.68-7.44 (m, 6H),6.75 (dd, J₁=5.6 Hz, J₂=10.8 Hz, 1H), 5.77-5.72 (m, 1H), 4.86-4.67 (m,3H); ESI-MS: m/z=530 [M+H]⁺.

Step 3. Compound of 16-4—

To a stirred solution of compound 16-3 (10.8 g, 20.4 mmol) in dry MeOH(100 mL) was added NaOMe (5.2 g, 96.3 mmol) and 2-mercapto-ethanol (6.7mL). The reaction mixture was stirred at refluxing overnight. The pHvalue was then adjusted to 9-10 with AcOH (conc.). The residue waswashed by MeOH to give compound 16-4 (pure, 5.1 g, yield 82.7%) as whitesolids. ¹H NMR (DMSO-d6, 400 MHz) δ 8.28 (s, 1H), 6.78 (s, 2H), 6.54 (t,J=6.8 Hz, 1H), 4.43-4.35 (m, 1H), 3.89-3.64 (m, 3H); ESI-MS: m/z=304[M+H]⁺.

Step 4. Compound 16-5—

To a stirred suspension of compound 16-4 (5.1 g, 16.8 mmol) in anhydrouspyridine (100 mL) was added Ac₂O (6.9 g, 67.3 mmol) at 0° C. The mixturewas stirred at R.T. for 18 hours. The reaction was then concentrated,and the residue was co-evaporated with pyridine. The residue wassuspended in anhydrous pyridine (100 mL). MMTrCl (10.4 g, 33.6 mmol) andAgNO₃ (5.7 g, 33.6 mmol) were added at R.T. The reaction mixture wasstirred for 18 hours, then quenched with water and extracted with EtOAc.The organic layer was dried over Na₂SO₄ and purified by silica gelcolumn to give compound 16-5 as white solids (7.2 g, 65%).

Step 5. Compound 16-6—

Compound 16-5 was dissolved in MeOH/NH3 at −70° C. The mixture wasstirred at R.T. for 18 hours. The solvent was concentrated, and theresidue was purified by silica gel column to give compound 16-6 (5.8 g,yield 59.9%) as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ 8.31 (s, 1H),7.48-7.6.83 (m, 14H), 6.45 (dd, J₁=4.0 Hz, J₂=10.0 Hz, 1H), 4.40-4.48(m, 1H), 3.93-3.98 (m, 2H); 3.77-3.81 (m, 1H), 3.75 (s, 3H); ESI-LCMS:m/z=576 [M+H]⁺.

Step 6. Compound 16-7—

To a stirred solution of compound 16-6 (5.8 g, 10.1 mmol) in dry THF(100 mL) were added imidazole (3.4 g, 50.4 mmol) and PPh₃ (13.6 g, 50.4mmol). A solution of I₂ (12.8 g, 50.4 mmol) in THF (30 mL) was addeddropwise under N₂ at 0° C. The mixture was stirred at R.T. for 18 hoursand then was quenched with Na₂S₂O₃ solution. The mixture was extractedwith EtOAc. The organic layer was dried by Na₂SO₄ and concentrated.Silica gel column chromatography give compound 16-7 (3.4 g, yield 49.2%)as a colorless solid. ¹H NMR (CD₃OD, 400 MHz) δ 8.06 (s, 1H), 7.13-7.36(m, 12H), 6.78 (d, J=8.8 Hz, 2H), 6.47 (dd, J₁=7.2 Hz, J₂=9.2 Hz, 1H),4.19-4.26 (m, 1H), 3.77-3.83 (m, 1H), 3.71 (s, 3H), 3.47-3.62 (m, 2H);ESI-MS: m/z=686 [M+H]⁺.

Step 7. Compound 16-8—

To a stirred solution of compound 16-7 (3.4 g, 5.0 mmol) in dry THF wasadded DBU (1.2 g, 7.5 mmol). The mixture was stirred at 60° C. for 8hours. The solution was quenched with a NaHCO₃ solution and extractedwith EtOAc. The organic layer was dried by Na₂SO₄ and concentrated. Theresidue was purified by a silica gel column to afford compound 16-8(2.10 g, yield 76.1%) as a colorless solid. ¹H NMR (CD₃OD, 400 MHz) δ8.00 (s, 1H), 7.19-7.68 (m, 12H), 6.82-6.86 (m, 2H), 6.74 (dd, J₁=6.0Hz, J₂=8.8 Hz, 1H), 4.95 (t, J=10 Hz, 1H), 4.74 (s, 1H); 4.55 (t, J=1.6Hz, 1H), 3.77 (s, 3H); ESI-MS: m/z=558 [M+H]⁺.

Step 8. Compound 16-9—

To a stirred solution of compound 16-8 (2.1 g, 3.8 mmol) in dry THF wereadded 4-methyl-morpholine (2.1 g, 20.8 mmol) and benzyl triethylammoniumazide (BnEt₃NN₃) (80.0 mL, 80.0 mmol in CH₃CN). A solution of I₂ (20.1 g78.7 mmol) in THF was added dropwise at 0° C. The mixture was stirred atR.T. for 18 hours. The solution was quenched with Na₂S₂O₃ solution andextracted with EtOAc. The organic layer was washed with a NaHCO₃solution, dried over Na₂SO₄ and concentrated to give the crude product.The crude product was dissolved in dry pyridine and BzCl (0.9 g, 6.6mmol) was added. The mixture was stirred at R.T. for 18 hours. Thesolution was quenched with NaHCO₃ solution, extracted with EtOAc. Theorganic layer was dried over Na₂SO₄ and concentrated. After purificationby silica gel column, compound 16-9 (2.0 g, yield 63.3%) was obtained asa white foam.

Step 9. Compound 16-10—

To a stirred solution of compound 16-9 (2.0 g, 2.4 mmol) in dry DMF wasadded NaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (3.4 mL, 17.4 mmol). Themixture was stirred at 100-105° C. for 48 hours. The solution wasdiluted with EA and filtered. The filtrate was washed with brine anddried over Na₂SO₄. The solvent was removed, and the residue was apurified by a silica gel column to afford compound 16-10 (crude, 540 mg,yield 27.1%).

Step 10. Compound 16-11—

Compound 16-10 (540 mg, 0.66 mmol) was dissolved in 80% AcOH solution,and the mixture was stirred at R.T. for 18 hours. The solution wasconcentrated and purified by a silica gel column to give compound 16-11(228 mg, crude).

Step 11. Compound (30)—

Compound 16-11 (228 mg) was dissolved in MeOH/NH₃. The mixture wasstirred at R.T. for 18 hours. The solvent was removed to give crude(30), which was purified on RP HPLC with MeOH/water to give 73.8 mg of(30) as an ivory solid; ¹H NMR (DMSO-d₆) δ 10.96 (br, 1H), 8.29 (s, 1H),6.71 (d, J=6.8 Hz, 1H), 6.62 (t, J=7.6 Hz, 1H), 6.29 (s, 2H), 5.78 (t,J=6.0 Hz, 1H), 4.85 (m, 1H), 3.87 (d, J=6.4 Hz, 2H); MS m/z=343.2[M−1]⁻.

Example 31 Preparation of 4′-azido-2′-deoxy-2′-fluoroguanosine5′-(O-phenyl-N—((S)-cyclohexoxycarbonyleth-1-yl))phosphoramidate (31)

To a solution of4′-azido-2′-fluoro-N²-(4-methoxytrityl)-2′-deoxyguanosine (50 mg, 0.084mmol) in THF (1.0 mL) under argon was added dropwise 1.0 M tert-BuMgClin THF (0.15 mL). The resulting solution was stirred at R.T. for 30 minand O-phenyl-N—(S)-1-(cyclohexoxycarbonyl)ethylphosphoramidic chloride(1.0 M in THF, 0.13 mL) was added. The reaction mixture was stirred atR.T. for overnight. The progress of the reaction was monitored by TLC.Additional 1.0 M tert-BuMgCl in THF (0.17 mL) followed by(O-phenyl-N—((S)-cyclopropoxycarbonyleth-1-yl))phosphoramidic chloride(1.0 M in THF, 0.17 mL) was added to the reaction mixture, and thereaction mixture was stirred for 2 days at R.T. The reaction mixture wasthen cooled with ice, quenched with aqueous ammonium chloride, dilutedwith ethyl acetate, washed with aqueous ammonium three times, dried oversodium sulfate, and concentrated. Chromatography on silica gel with 5-7%MeOH in DCM gave a mixture of two isomers as an off-white foam (30.1mg). The obtained product was dissolved in 80% formic acid (2 mL), andthe resulting solution stood at R.T. for 3 hours. The solvent wasevaporated at R.T. and co-evaporated with MeOH/toluene three times.Purification on reverse-phase HPLC (C18) using acetonitrile and water,followed by lyophilization, gave (31) (6.3 mg) as a white foam; ¹H NMR(CD₃OD, two isomer) δ 1.24-1.76 (m, 13H), 3.78-3.88 (m, 1H), 4.28-4.38(m, 1H), 4.39-4.44 (m, 1H), 4.64-4.66 (m, 1H), 5.09, 5.14 (each dd,J=2.8, 5.2 Hz, 1H), 5.09, 5.14 (each dd, J=2.8, 5.2 Hz, 1H), 5.42-5.47 &5.55-5.6 (2×m, 1H), 6.37, 6.43 (each dd, J=2.0, 6.0 Hz, 1H), 7.09-7.31(m, 5H), 7.85 (s, 1H); ³¹P NMR (CD₃OD, two isomers) δ 3.53 (s), 3.46(s); ESI-LCMS m/z=634.5 [M+H]⁺.

Example 32 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine3′,5′-cyclic phosphate (32)

1,2,4-Triazol (21 mg, 0.3 mmol) was suspended in 0.7 mL of dry CH₃CN.

Triethylamine was added (0.046 mL, 0.33 mmol), and the mixture wasvortexed to obtain a clear solution. After addition of POCl₃ (0.01 mL,0.1 mmol), the mixture was vortexed and left for 20 min, and thencentrifuged. The supernatant was added to4′-azido-2′-deoxy-2′-fluorouridine (14 mg, 0.05 mmol), and the mixturewas kept at ambient temperature for 1 hour. The reaction was quenchedwith water, and the phosphate was isolated by IE chromatography on anAKTA Explorer using column HiLoad 16/10 with Q Sepharose HighPerformance. Separation was done in a linear gradient of NaCl from 0 to1 N in 50 mM TRIS-buffer (pH 7.5). The fractions eluted at 50-60% NaClwere combined, concentrated and desalted by RP HPLC on Synergy 4 micronHydro-RP column (Phenominex). A linear gradient of methanol from 0 to30% in 50 mM triethylammonium buffer was used for elution over 20 min,flow 10 ml/min. Three compounds corresponding to the 5′-monophosphate,3′,5′-diphosphate, and (32) were collected. ¹H NMR (D₂O) δ 7.50-7.49 (d,1H), 6.05-6.00 (d, 1H), 5.73-5.71 (d, 1H), 5.50-5.35 (dd, 1H), 4.98-4.89(m, 1H), 4.49-4.34 (m, 2H); ³¹P NMR: δ3.45s; LCMS: m/z 348.2 [M−H]⁻.

Example 33 Preparation of 4′-azido-2′-deoxy-2′-difluorocytidine5′-(N,N′-bis((S)-1-(isopropoxycarbonyl)ethyl))phosphordiamidate (33)

To a stirred of suspension of phosphorous oxychloride (10.0 g, 65.7mmol) and L-aniline isopropyl ester (21.97 g, 131.5 mmol) in anhydrousDCM (400 mL) was added a solution of TEA (26.57 g, 263 mmol) in DCM (15mL) dropwise at −78° C. After addition, the mixture was warmed to R.T.and then stirred 6 hours. The solvent was removed, and the residue wasdissolved in methyl-butyl ether. The precipitate was removed byfiltration, and the filtrate was concentrated to give the crudecompound, which was purified on a silica gel column to give(N,N′-bis((S)-1-(isopropoxycarbonyl)ethyl))phosphordiamidic chloride(5.6 g, yield: 27.35%) as colorless oil. To a solution of compound (1)(90 mg, 0.3 mmol) in anhydrous THF (5 mL) was added a solution oft-BuMgCl (0.50 mL, 1M in THF) dropwise at −78° C. The mixture was thenstirred at R.T. for 30 min and re-cooled to −78° C. A solution ofN,N-bis((S)-1-(isopropoxycarbonyl)ethyl)phosphordiamidic chloride (0.50mL, 1M in THF) was added dropwise. After addition, the mixture wasstirred at R.T. for 14 hours. The reaction was quenched with HCOOH. Thesolvent was removed, and the residue was purified by prep. HPLC (0.1%HCOOH in MeCN and water) to give (33) (22.6 mg, 12.5%) as a white solid.¹H NMR (CD₃OD, 400 MHz) δ 7.64 (d, J=7.6 Hz, 1H), 6.45 (br s, 1H), 6.02(d, J=7.6 Hz, 1H), 4.97-5.06 (m, 2H), 4.61 (t, J=12.0 Hz, 1H), 4.34 (d,J=6.4 Hz, 2H), 3.86-3.97 (m, 2H), 1.35-1.41 (m, 6H), 1.24-1.27 (m, 12H);³¹P NMR (CD₃OD, 162 MHz) δ 13.81; ESI-LCMS: m/z 611 [M+H]⁺.

Example 34 Preparation of 4′-azidoarabinocytidine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (34)

To a solution of compound (11) (90 mg, 0.32 mmol) in anhydrous THF (3mL) was added a solution of t-BuMgCl (0.65 mL, 1M in THF) dropwise at−78° C. The mixture was then stirred at R.T. for 30 min and cooled to−78° C. A solution ofO-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidic chloride (0.65mL, 1M in THF) was added dropwise. After addition, the mixture wasstirred at R.T. for 14 hours. The reaction was quenched with formic acid(3 mL) and concentrated. The residue was purified by HPLC to givecompound (34) (4.5 mg, 2.5%). ¹H NMR (CD₃OD, 400 MHz) δ 7.66 (d, J=7.6Hz, 1H), 7.35-7.39 (m, 2H), 7.17-7.28 (m, 3H), 6.49 (d, J=7.2 Hz, 1H),5.85 (d, J=7.2 Hz, 1H), 4.94-4.99 (m, 1H), 4.35-4.42 (m, 2H), 4.24-4.28(m, 1H), 4.13 (d, J=3.6 Hz, 1H), 3.90-3.95 (m, 1H), 1.34 (d, J=7.2 Hz,3H), 1.21-1.23 (m, 6H); ³¹P NMR (CD₃OD, 162 MHz) δ 3.59, 3.44; ESI-LCMS:m/z 554 [M+H]⁺.

Example 35 Preparation of 4′-azidoarabinouridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (35)

Compound 35 (white solid, 18.3 mg, 11%) was prepared using the procedurefor preparing compound 34 with (compound (12), 86 mg, 0.30 mmol) inplace of compound (11), t-BuMgCl (0.60 mL, 1M in THF), and (S)-phenyl5-methyl-3-oxohexan-2-ylphosphoramidochloridate (0.60 mL, 1M in THF). ¹HNMR (CD₃OD, 400 MHz) δ 77.61-7.67 (m, 1H), 7.36-7.41 (m, 2H), 7.20-7.29(m, 3H), 6.43 (d, J=4.8 Hz, 1H), 5.58-5.67 (m, 1H), 4.96-5.02 (m, 1H),4.28-4.50 (m, 2H), 4.19 (d, J=4.0 Hz, 1H), 3.92-3.97 (m, 1H), 1.36 (d,J=7.2 Hz, 3H), 1.23-1.26 (m, 6H); ³¹P NMR (CD₃OD, 162 MHz) δ 3.57, 3.45;ESI-LCMS: m/z 555 [M+H]⁺.

Example 36 Preparation of 4′-azido-2′-deoxy-2′-methylarabinouridine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (36)

To a stirred solution of compound (6) (56 mg, 0.2 mmol) in dry THF (5mL) was added t-BuMgCl (1M in THF, 0.45 mL) dropwise at −78° C. Thesolution was warmed to R.T., and the mixture was stirred for 20 min. Themixture was cooled to −78° C. andO-phenyl-N—(S)-1-(isopropoxycarbonyl)ethylphosphoramidic chloride (1M inTHF, 0.40 mL) was added. The mixture was then warmed to R.T. graduallyand stirred for 3 hours. The reaction was quenched by HCOOH andconcentrated. The residue was purified on a silica gel column to give(36) as a white solid (8.3 mg, 7.6%). ¹H NMR (CD₃OD, 400 MHz) δ7.57-7.59 (m, 1H), 7.37-7.41 (m, 2H), 7.21-7.30 (m, 3H), 6.38 (br s,1H), 5.65-5.67 (m, 1H), 4.95-4.99 (m, 1H), 4.45-4.49 (m, 2H), 4.07 (brs, 1H), 3.92-3.96 (m, 1H), 2.73-2.79 (m, 1H), 1.33-1.37 (m, 3H),1.22-1.23 (m, 6H), 0.98-1.02 (m, 3H); ³¹P NMR (CD₃OD, 162 MHz) δ 3.56,3.45; ESI-LCMS: m/z=575 [M+Na]⁺.

Example 37 Preparation of 4′-azido-2′-deoxy-2′-fluoroadenosine5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)phosphoramidate (37)

Step 1. Compound 28-2—

To an ice-cold solution of (28) (240 mg, 0.77 mmol) in anhydrouspyridine (10 mL) was added TBSCl (318 mg, 1.16 mmol) in small portionsunder N₂. The reaction mixture was stirred at R.T. overnight. Thesolvent was removed under vacuum, and the residue was diluted with EA(50 mL), and washed with water and brine. The organic layer wasseparated, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuum to give a residue which was purified by silicagel column (DCM/MeOH=100/1 to 50/1) to give compound 28-2 (233 mg, 52%).ESI-LCMS: m/z=549 [M+H]⁺.

Step 2. Compound 28-3—

To a mixture of compound 28-2 (233 mg, 0.42 mmol), AgNO₃ (288 mg, 1.70mmol) and collidine (205 mg, 1.70 mmol) in anhydrous pyridine (10 mL)was added MMTrCl (523 mg, 1.70 mmol) under N₂. The reaction mixture wasstirred at R.T. overnight under N₂. The reaction mixture was filtered,and the solvent was removed under vacuum. The residue was diluted withEA, and washed with water and brine. The filtrate was washed withsaturated aqueous NaHCO₃ and followed by brine. The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated to give aresidue which was purified on silica gel column to give compound 28-3(350 mg, 75%). ESI-LCMS: m/z=1093 [M+H]⁺.

Step 3. Compound of 28-4—

To the solution of compound 28-3 (350 mg, 0.32 mmol) in anhydrous THFwas added TBAF (167 mg, 0.64 mmol) dropwise under N₂. The reactionmixture was stirred at R.T. overnight. The solvent was removed. Theresidue was dissolved in EA (200 mL), and washed with water and brine.The organic layer was separated, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuum to give a residuewhich was purified on silica gel column (DCM/MeOH=100/1 to 80/1) to givecompound 28-4 (195 mg, 71%). ESI-LCMS: m/z=855 [M+H]⁺.

Step 4. Compound 28-5—

To a stirred compound 28-4 (195 mg, 0.23 mmol) in anhydrous THF (5 mL)was added a solution of t-BuMgCl (0.70 mL, 0.70 in THF) dropwise at 0°C. The mixture was then stirred at R.T. for 40 min and cooled to 0° C. Asolution of O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethylphosphoramidicchloride (0.70 mL, 1M in THF) was added dropwise. After addition, themixture was stirred at R.T. for 12 hours. The reaction was quenched withwater and extracted with EA. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by column on silica gel(PE:EA=5:1 to 2:1) to give compound 28-5 (103 mg, 40%). ESI-LCMS:m/z=1123 [M+H]⁺.

Step 5. Compound (37)—

Compound 28-5 (103 mg, 0.10 mmol) was dissolved in 5 mL AcOH/H₂O(v/v=4:1). The mixture was stirred at 50° C. overnight. The solvent wasremoved under vacuum, and the residue was purified on silica gel columnto give (37) as a white solid (9 mg, 16%). ¹H NMR (CDCl₃, 400 MHz) 58.25(S, 1H), 7.92 (S, 1H), 7.25˜7.29 (m, 2H), 7.11˜7.15 (m, 3H), 6.34 (d,J=19.6 Hz, 1H), 5.82 (bs, 2H), 5.49˜5.64 (m, 1H), 5.29˜5.35 (m, 1H),4.94˜4.99 (m, 1H), 4.46˜4.51 (m, 1H), 4.33˜4.38 (m, 1H), 3.89˜3.94 (m,2H), 1.28˜1.32 (m, 3H), 1.21˜1.18 (m, 6H). ³¹P NMR (CDCl₃, 162 MHz) δ2.63, 2.55. ESI-LCMS: m/z=580 [M+H]⁺.

Example 38 Preparation of4′-azido-2′-deoxy-2′-a-fluoro-2′-β-methylcytidine (38)

Step 1. Compound 10-2—

To a stirred suspension of compound 10-1 (1.46 g, 5.62 mmol), PPh₃(4.413 g, 16.84 mmol) and pyridine (5 mL) in anhydrous THF (40 mL) wasadded dropwise a solution of I₂ (2.852 g, 11.23 mmol) in THF (20 mL) at0° C. After addition, the mixture was warmed to R.T. and stirred for 14hours. The solution was quenched with saturated aqueous Na₂S₂O₃ (100 mL)and extracted with EA (100 mL 3 times). The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(DCM/MeOH=100:1 to 50:1) to afford compound 10-2 as a white solid (1.51g, 72.4%).

Step 2. Compound 10-3—

Compound 10-2 (150 mg, 0.41 mmol) and CH₃ONa (66 mg, 1.22 mmol) weredissolved in anhydrous methanol (10 mL). The mixture was stirred at 60°C. for 12 hours. The reaction was quenched with CO₂. The solvent wasremoved, and the residue was purification on a silica gel column(MeOH/DCM=1/50 to 1/10) to afford compound 10-3 as a white solid (52 mg,50.9%).

Step 3. Compound 10-4—

To a stirred solution of BnEt₃NCl (1.169 g, 5.02 mmol) in MeCN (10 mL)was added NaN₃ (0.326 g, 5.02 mmol). The mixture was sonicated for 20min and then stirred at R.T. for 16 hours. The solution was filtratedinto a solution of compound 10-3 (0.15 g, 0.619 mmol) and NMM (0.626 g,6.19 mmol) in anhydrous THF (10 mL). The mixture was cooled to 0° C. anda solution of I₂ (1.574 g, 5.02 mmol) in THF (5 mL) was added dropwise.Stirring was continued at 0-10° C. for 20 hours. N-Acetyl cystein wasadded until no gas evolved. Saturated aqueous Na₂S₂O₃ was added until alight yellow solution achieved. The solution was concentrated and thendiluted with EA. The organic phase was washed with brine and dried overNa₂SO₄. The solvent was removed, and the residue was purified on asilica gel column (DCM:MeOH=50:1 to 10:1) to give compound 10-4 (0.183g, 70.8%) as a white solid.

Step 4. Compound 10-5—

To a stirred solution of compound 10-4 (0.6 g, 1.46 mmol) in anhydrouspyridine (15 mL) was added BzCl (0.408 mg, 2.92 mmol) dropwise at 0° C.The mixture was stirred at R.T. for 10 hours. The reaction was quenchedwith H₂O and the solution was concentrated. The residue was dissolved inEA and washed with Sat. aqueous NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(PE/EA=10/1 to 1/1) to give 10-5 (0.22 g, 26.6%) as light yellow foam.

Step 5. Compound 10-6—

Compound 5 (100 mg, 0.194 mmol), BzONa (279 mg, 1.94 mmol) and15-crown-5 (427 mg, 1.94 mmol) were suspended in DMF (20 mL). Themixture was stirred at 95° C. for 1 day. The precipitate was removed byfiltration, and the filtrate was diluted with EA. The solution waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (PE/EA=4/1 to 2/1) toafford compound 10-6 (87 mg, 88.1%).

Step 6. Compound 10-7—

A solution of compound 10-6 (200 mg, 0.39 mmol), DMAP (95.87 mg, 0.79mmol) and TEA (79.36 mg, 0.79 mmol) in MeCN (15 mL) was treated with2,4,6-triispropylbenzenesulfonyl chloride (TPSCl, 237.3 mg, 0.79 mmol).The mixture was stirred at R.T. for 12 hours. To the mixture was addedNH₃ in THF (50 mL), and the mixture was stirred for additional 2 hours.The solution was evaporated under reduced pressure, and the residue waspurified on a silica gel column (DCM/MeOH=100:1 to 10:1) to givecompound 10-7.

Step 7. Compound (38)—

Compound 10-7 (0.15 g, 0.295 mmol) was dissolved in methanolic ammonia(30 mL), and the mixture was stirred at R.T. for 14 hours. The solventwas removed, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to give (38) as a white solid (29 mg, 35.5%). ¹HNMR (CD₃OD, 400 MHz) δ 8.01 (s, 1H), 6.56 (d, J=18.0 Hz, 1H), 5.94 (d,J=7.6 Hz, 1H), 4.14 (d, J=7.6 Hz, 1H), 3.87 (d, J=7.6 Hz, 1H), 3.75 (d,J=7.6 Hz, 1H), 1.28 (dd, J₁=31.6 Hz, J₂=7.2 Hz, 3H); ESI-MS: m/z=301.1[M+H]⁺.

Example 39 Preparation of 4′-azido-2′-deoxy-2′-difluorouridine5′-(N,N-bis((S)-isopropoxycarbonyleth-1-yl))phosphordiamidate (39)

To a solution of compound (5) (90 mg, 0.29 mmol) in anhydrous THF (5 mL)was added a solution of t-BuMgCl (0.5 mL, 1M in THF) dropwise at −78° C.The mixture was then stirred at R.T. for 30 min and cooled to −78° C. Asolution of N,N′-bis((S)-1-(isopropoxycarbonyl)ethyl)phosphordiamidicchloride (0.5 mL, 1M in THF) was added dropwise. After addition, themixture was stirred at R.T. for 14 hours. The reaction was quenched withHCOOH. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by HPLC to give (39) (27.1 mg, 14.3%) as a whitesolid. ¹H NMR (CD₃OD, 400 MHz) δ7.62 (d, J=8.0 Hz, 1H), 6.32 (t, J=7.6Hz, 1H), 5.82 (d, J=8.0 Hz, 1H), 4.95-5.01 (m, 2H), 4.64 (t, J=12.8 Hz,1H), 4.27-4.36 (m, 2H), 3.82-3.98 (m, 2H), 1.37 (d, J=7.2 Hz, 3H),1.23-1.26 (m, 6H); ³¹P NMR (CD₃OD, 162 MHz) δ 13.83. ESI-LCMS: m/z=612[M+H]⁺.

Example 40 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine5′-(N,N′-bis((S)-1-isopropoxycarbonyl)ethyl))phosphordiamidate (40)

Compound 40 (white solid, 24.8 mg, 13.93%) was prepared using theprocedure for preparing compound 39 with (compound (17), 86 mg, 0.3mmol) in place of compound (5), t-BuMgCl (0.55 mL, 1M in THF), and(N,N-bis((S)-isopropoxycarbonyleth-1-yl))phosphordiamidic chloride (0.55mL, 1M in THF). ¹H NMR (CD₃OD, 400 MHz) δ 7.70 (d, J=8.0 Hz, 1H), 6.09(dd, J₁=2.0 Hz, J₂=20.4 Hz, 1H), 5.76 (d, J=8.0 Hz, 1H), 5.30 (ddd,J₁=2.0 Hz, J₂=5.6 Hz, J₃=53.6 Hz, 1H), 4.94-5.01 (m, 2H), 4.70 (dd,J₁=5.6 Hz, J₂=20.4 Hz, 1H), 4.13-4.27 (m, 2H), 3.81-3.90 (m, 2H), 1.36(d, J=7.2 Hz, 3H), 1.22-1.25 (m, 6H); ³¹P NMR (CD₃OD, 162 MHz) δ 13.69.ESI-LCMS: m/z=594 [M+H]⁺.

Example 41 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine3′,5′-cyclic thiophosphoric acid methyl ester (41)

To an ice-cold suspension of compound (17) (150 mg, 0.52 mmol) in drypyridine (4 mL) was added tetrazole (0.37 M in MeCN, 4 mL, 1.48 mmol),followed by addition of methyl N,N,N′,N′-tetraisopropylphosphordiamidite(204 mg, 0.78 mmol) dropwise over 5 min. The resultant mixture wasstirred at the ambient temperature for 16 hours beforebis(3-triethoxysilyl)propyl-tetrasulfide (TEST) (0.42 mL, 0.8 mmol) wasadded. The resulting light yellow suspension was stirred for 3 hours atR.T. The reaction mixture was cooled down (ice/water bath), and wasdiluted with EA (100 mL), washed with saturated NaHCO₃ and followed bybrine, dried over anhydrous Na₂SO₄ and concentrated in-vacuo to givecrude product residue. The crude product was purified by flashchromatography on silica gel and then further purified on HPLC to give(41) (21.2 mg, 11%) as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ7.69 (d,J=8.0 Hz, 1H), 6.06 (d, J=22.0 Hz, 1H), 5.71 (d, J=8.0 Hz, 1H),5.67-5.52 (dd, J=55.6 Hz, 5.6 Hz, 1H), 5.35-5.26 (dt, J=25.6 Hz, 4.0 Hz,1H), 4.66 (m, 2H), 3.85 (d, J=13.6 Hz, 3H). ³¹P NMR (CD₃OD, 162 MHz)δ62.66. ESI-LCMS: m/z=402 [M+Na]⁺.

Example 42 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine3′,5′-cyclic thiophosphoric acid isopropyl ester (42)

Compound 42 (white solid, 15.5 mg, 7.4%) was prepared using theprocedure for preparing compound 41 using (compound (5), 150 mg, 0.49mmol) in place of compound (17), and isopropylN,N,N′,N′-tetraisopropylphosphordiamidite (213 mg, 0.74 mmol). ¹H NMR(CD₃OD, 400 MHz) δ7.73 (d, J=6.8 Hz, 1H), 6.35 (br, 1H), 5.77 (d, J=8.0Hz, 1H), 5.35 (br, 1H), 4.92 (m, 1H), 4.78 (m, 2H), 1.40 (t, 6H). ³¹PNMR (CD₃OD, 162 MHz) δ58.53. ESI-LCMS: m/z 426 [M+H]⁺.

Example 43 Preparation of 4′-azidoribavirin (43)

Step 1. Compound 14-2—

A solution of PPh₃ (17.48 g, 66.6 mmol) and I₂ (15.61 g, 61.5 mmol) inpyridine (100 mL) was stirred at R.T. for 20 min and then compound 14-1(10.0 g, 41.0 mmol) was added. The reaction mixture was stirred at R.T.for 12 hours, concentrated to dryness, and co-evaporated with toluenetwice. The crude product was purified on a silica gel column(DCM/MeOH=20:1 to 7.5:1) to afford compound 14-2 (8.21 g, 56.5%).

Step 2. Compound 14-3—

Compound 14-2 (200 mg, 0.56 mmol) and CH₃ONa (305 mg, 5.65 mmol) weredissolved in anhydrous methanol (10 mL). The mixture was stirred at 60°C. for 12 h. The solvent was removed, and the residue was co-evaporatedwith MeCN. The residue was re-dissolved in MeCN and Ac₂O (1.15 g, 11.298mmol) was added. The suspension was heated to 60° C. and stirred for 5hours. After cooling, the solution was adjusted to pH=7.5 by slowaddition of a saturated aqueous NaHCO₃. The mixture was extracted withEA and brine. The organic phase was concentrated and purified on asilica gel column (MeOH/DCM=1/50 to 1/10) to afford compound 14-3 as awhite solid (102 mg, 57.1%).

Step 3. Compound 14-4—

Compound 14-3 (0.10 g, 0.32 mmol) was dissolved in methanolic ammonia(30 mL), and the mixture was stirred at R.T. for 14 hours. The solventwas removed, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to give compound 14-4 as a white solid (51 mg,68.7%).

Step 4. Compound 14-5—

To a stirred solution of BnEt₃NCl (1.169 g, 5.02 mmol) in MeCN (10 mL)was added NaN₃ (0.326 g, 5.02 mmol). The mixture was sonicated for 20min and then stirred at R.T. for 16 hours. The solution was filtratedinto a solution of compound 14-4 (0.20 g, 0.885 mmol) and NMM (0.447 g,4.424 mmol) in anhydrous THF (10 mL). The mixture was cooled to 0° C.,and a solution of I₂ (1.123 g, 4.43 mmol) in THF (5 mL) was addeddropwise. Stirring was continued at 0-10° C. for 20 hours. The reactionmixture was cooled to 0° C., and DMAP (90 mg, 0.885 mmol) and BzCl (619mg, 4.42 mmol) were added. The mixture was stirred at R.T. for 4 hoursand then diluted with EA. N-Acetyl cystein was added until no gasevolved. Saturated Na₂S₂O₃ in aqueous NaHCO₃ was added until a lightyellow solution was achieved. The solution was concentrated and thendiluted with EA. The organic phase was washed with brine and dried overNa₂SO₄. The solvent was removed, and the residue was purified on asilica gel column (DCM:MeOH=50:1 to 10:1) to give compound 14-5 (0.351g, 57.2%) as a white solid.

Step 5. Compound 14-6—

Compound 14-5 (300 mg, 0.498 mmol), BzONa (716 mg, 4.98 mmol) and15-crown-5 (1.094 g, 4.98 mmol) were suspended in DMF (60 mL). Themixture was stirred at 95° C. for 1 day. The precipitate was removed byfiltration, and the filtrate was diluted with EA. The solvent was washedwith brine and dried over Na₂SO₄. The solvent was removed, and theresidue was purified by column (PE/EA=4/1 to 2/1) to afford compound14-6 (199 mg, 67.3%).

Step 6. Compound (43)—

Compound 14-6 (1.51 g, 2.49 mmol) was dissolved in methanolic ammonia(50 mL), and the solution was stirred at R.T. for 14 hours. The solventwas removed, and the residue was purified on a silica gel column(DCM/MeOH=30:1 to 10:1) to give (43) as a white solid (403 mg, 56.4%).¹H NMR (DMSO-d₆, 400 MHz) δ8.93 (s, 1H), 7.90 (s, 1H), 7.66 (s, 1H),6.10 (d, J=4.8 Hz, 1H), 5.81 (d, J=6.4 Hz, 2H), 5.39 (t, J=6.0 Hz, 1H),4.59 (q, J=5.6 Hz, 1H), 4.37 (dd, J₁=6.0 Hz, J₂=5.2 Hz, 1H), 3.51-3.57(m, 1H), 3.35-3.45 (m, 1H); ESI-MS: m/z=308 [M+Na]⁺.

Example 44 Preparation of 4′-azidouridine5′-(N,N′-bis((S)-1-(isopropoxycarbonyl)ethyl))phosphorodiamidate (44)

To a stirred solution of 19-2 (100 mg, 0.3 mmol) in anhydrous THF (5 mL)was added a solution of t-BuMgCl (0.6 mL, 1M in THF) dropwise at −78° C.The mixture was then stirred at R.T. for 30 min and cooled to −78° C. Asolution of N,N′-bis((S)-1-(isopropoxycarbonyl)ethyl)phosphordiamidicchloride (0.6 mL, 1M in THF) was added dropwise. After addition, themixture was stirred at R.T. for 16 hours. The reaction was quenched withH₂O and extracted with EA. The solvent was concentrated, and the residuewas purified on silica gel (PE:EA=2:1) to give an intermediate (80 mg,41.4%). The intermediate (80 mg, 0.13 mmol) was dissolved in 60% formicacid aqueous solution, and the resulting mixture was stirred at R.T. for50 hours. The solvent was removed, and the residue was purified on HPLCto give (44) (6.5 mg, 8.3%) as a white solid. ¹H NMR (DMSO-d6, 400 MHz)δ7.73 (d, J=7.6 Hz, 1H), 6.08 (d, J=6.4 Hz, 1H), 6.03 (br s, 1H), 5.69(d, J=8.0 Hz, 1H), 5.66 (br s, 1H), 4.95-5.04 (m, 2H), 4.86-4.88 (m,2H), 4.26 (br s, 2H), 3.72-3.85 (m, 4H), 1.24 (d, J=7.2 Hz, 3H),1.17-1.20 (m, 6H). ³¹P NMR (DMSO-d6, 162 MHz) δ12.82. ESI-LCMS: m/z=592[M+H]⁺.

Example 45 Preparation of 4′-azido-2′-deoxy-2′-fluorouridine3′,5′-cyclic thiophosphoric acid isopropyl ester (45)

To an ice-cold suspension of compound (17) (100 mg, 0.35 mmol) in drypyridine (3 mL) was added tetrazole (0.37 M in MeCN, 3 mL, 1.11 mmol),followed by addition of isopropylN,N,N′,N′-tetraisopropylphosphordiamidite (151 mg, 0.52 mmol) dropwiseafter 5 min. The resultant mixture was stirred at the ambienttemperature for 16 hours before TEST (0.42 mL, 0.8 mmol) was added. Theresulting light yellow suspension was stirred for 3 hours at R.T. Thereaction mixture was cooled down (ice/water bath), diluted with EA (100mL), washed with saturated NaHCO₃ aq. and followed by brine, dried overanhydrous Na₂SO₄ and concentrated in-vacuo to give a crude productresidue. The crude product was purified on silica gel (DCM/MeOH; 95:5)and then further purified on HPLC to give (45) (30.5 mg, 21.6%) as awhite solid. ¹H NMR (CD₃OD, 400 MHz) δ7.70 (d, J=8.0 Hz, 1H), 6.15 (d,J=22.4 Hz, 1H), 5.71 (d, J=8.0 Hz, 1H), 5.62 (dd, J₁=5.2 Hz, J₂=55.6 Hz,1H), 5.38-5.47 (m, 1H), 4.80-4.85 (m, 1H), 4.59-4.71 (m, 2H), 1.39-1.41(m, 6H); ³¹P NMR (CD₃OD, 162 MHz) δ59.36; ESI-LCMS: m/z=430 [M+Na]⁺.

Example 46 Preparation of 4′-azido-2′-deoxy-2′-fluorocytidine3′,5′-cyclic thiophosphoric acid isopropyl ester (46)

Compound 46 (white solid, 7.2 mg, 8.5%) was prepared using the procedurefor preparing compound 45 using (compound (2), 60 mg, 0.21 mmol) inplace of compound (17), and isopropylN,N,N′,N′-tetraisopropylphosphordiamidite (92 mg, 0.32 mmol). ¹H NMR(CD₃OD, 400 MHz) δ7.69 (d, J=7.6 Hz, 1H), 5.87-5.93 (m, 2H), 5.58-5.67(m, 1H), 5.50-5.54 (m, 1H), 4.81-4.84 (m, 1H), 4.62-4.69 (m, 2H), 1.41(t, J=6.0 Hz, 6H); ³¹P NMR (CD₃OD, 162 MHz) δ59.58; ESI-LCMS: m/z 407[M+H]⁺.

Example 47 Preparation of 4′-azidoarabinoguanosine (47)

Step 1. Compound 15-2—

To a stirred solution of compound 15-1 (5.0 g, 17.7 mmol) in dry DMF (30mL) were added imidazole (2.4 mL, 35.4 mmol) and TBSCl (5.3 g, 35.4mmol) at 0° C. The mixture was then stirred at R.T. for 18 hour. Thereaction mixture was cooled to 0° C. and quenched with ice water. Theresulting precipitate was collected and washed with water and acetone togive compound 15-2 (6.3 g, yield 89.8%) as a white solid. ¹H NMR(DMSO-d6, 400 MHz) δ 10.58 (s, 1H), 7.69 (s, 1H), 6.46 (s, 2H), 5.99 (d,J=4.4 Hz, 1H), 5.62 (d, J=4.8 Hz, 1H), 5.52 (d, J=4.4 Hz, 1H), 4.04-4.09(m, 2H), 3.71-3.85 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H); ESI-MS: m/z=398[M+H]⁺.

Step 2. Compound 15-3—

To a stirred suspension of compound 15-2 (6.3 g, 182.39 mmol) in drypyridine (80 mL) was added Bz₂O (42.0 g, 185.8 mmol). The mixture wasstirred at R.T. for 48 hours. The reaction mixture was diluted with DCM(200 mL). The precipitate was collected and washed with DCM to givecompound 15-3 (7.8 g, yield 81.4%) as a white solid. ¹H NMR (DMSO-d6,400 MHz) δ 10.60 (s, 1H), 7.44-8.04 (m, 11H), 6.44-6.46 (m, 3H), 5.99(t, J=5.2 Hz, 1H), 5.89 (t, J=6.4 Hz, 1H), 4.40 (d, J=5.6 Hz, 1H),3.98-4.05 (m, 2H), 0.86 (s, 9H), 0.05 (s, 6H); ESI-MS: m/z=606 [M+H]⁺

Step 3. Compound 15-4—

To a stirred solution of compound 15-3 (7.8 g, 12.9 mmol) in dry DCM(100 mL) was added TsOH (monohydrate, 3.3 g, 19.3 mmol) at 0° C. Themixture was stirred at 0° C. for 2 hours. The reaction was quenched withNaHCO₃ solution, extracted with DCM. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on silica gel columnto afford compound 15-4 (5.2 g, yield 82.1%) as a white solid. ¹H NMR(DMSO-d6, 400 MHz) δ 10.59 (s, 1H), 7.41-8.01 (m, 11H), 6.39-6.44 (m,3H), 5.86 (dd, J₁=4.4 Hz, J₂=5.6 Hz, 1H), 5.78 (dd, J₁=4.0 Hz, J₂=5.6Hz, 1H), 4.30-4.32 (m, 1H), 3.75-3.81 (m, 2H); ESI-MS: m/z=492 [M+H]⁺.

Step 4. Compound 15-5—

To a stirred solution of compound 15-4 (5.2 g, 10.6 mmol), imidazole(2.9 g, 42.4 mmol) and PPh₃ (8.3 g, 31.8 mmol) in dry THF (100 mL) wasadded dropwise a solution of I₂ (8.1 g, 31.8 mmol) in dry THF (50 mL)under N₂ at 0° C. The reaction mixture was stirred at R.T. overnight.The reaction was quenched with Na₂S₂O₃ solution and extracted withEtOAc. The organic layer was dried over Na₂SO₄ and concentrated.Purification on silica gel column gave compound 15-5 (4.6 g, yield72.3%) as a white solid. ¹H NMR (DMSO-d6, 400 MHz) δ 10.66 (s, 1H),7.46-8.06 (m, 11H), 6.49-6.51 (m, 3H), 5.98 (t, J₁=4.8 Hz, J₂=5.6 Hz,1H), 5.81 (t, J=5.2 Hz, 1H), 4.43-4.47 (m, 1H), 3.69-3.81 (m, 2H);ESI-MS: m/z=602 [M+H]⁺.

Step 5. Compound 15-6—

A mixture of MMTrCl (3.09 g, 10 mmol) and silver nitrate (2.83 g, 11mmol) in 20 mL of pyridine was stirred at R.T. for 1 hour. Compound 15-5(2.67 g, 4.45 mmol) in DMF (15 mL) was added, and the resulting mixturewas stirred at R.T. for 6 hours. Additional MMTrCl (3.09 g) and silvernitrate (2.83 g) were added, and the mixture was stirred at R.T. for 3days. The mixture was diluted with EA, and the precipitate was filtered.The filtrate was washed with brine 5 times, dried over sodium sulfate,and concentrated. Purification on silica gel column with 3-6% i-PrOH inDCM gave compound 15-6 (2.64 g) as a white foam.

Step 6. Compound 15-7—

A solution of compound 15-6 (2.64 g, 3.02 mmol) and DBU (3.93 mmol) inTHF (30 mL) was heated at 55-57° C. for 6 hours. The mixture was thencooled to R.T., diluted with EA, washed brine (3 times), dried oversodium sulfate, and concentrated. Purification on silica gel column with3-6% i-PrOH in DCM gave an olefinyl intermediate, which was dissolved in7 M NH₃ in MeOH. The solution stood at R.T. overnight and concentrated.Purification on silica gel column with 5-7% i-PrOH in DCM gave compound15-7 (1.20 g) as a white foam.

Step 7. Compound 15-8—

A mixture of BnEt₃NCl (1.03 g, 4.5 mmol) and NaN₃ (306 mg, 4.95 mmol) inanhydrous MeCN (50 mL) was sonicated for 10 min and then stirred at R.T.for 6 hours. The solution was taken out by syringe to another flask andconcentrated to about 20 mL. The solution was added to a stirredsolution of compound 15-7 (730 mg, 1.34 mmol) and NMM (50 uL, 0.45 mmol)in THF (15 mL). The solution was cooled with ice, and a solution of I₂(590 mg, 2.3 mmol) in THF (13 mL) was added. The resulting reactionmixture was stirred at R.T. for 16 hours. After the mixture was cooledwith ice, 5% of aqueous Na₂S₂O₃ (95 mL) was added. The mixture wasdiluted with EA, washed with 5% aqueous Na₂S₂O₃ twice and with brineonce, dried over sodium sulfate, and concentrated to give a foam(crude). A solution of the crude and pyridine (1.1 mL, 13.4 mmol) wasadded to a mixture of BzCl (0.64 mL, 5.36 mmol) and silver nitrate (1.4g, 5.36 mmol) in DMF (15 mL) previously stirred at R.T. for 1 hour. Theresulting reaction mixture was stirred at R.T. overnight, diluted withEA, and filtered to remove the precipitate. The filtrate was washed withbrine 5 times, dried over sodium sulfate, and concentrated. Purificationon silica gel column with 0-3% i-PrOH in DCM gave compound 15-8 (0.72 g,crude).

Step 8. Compound 15-9—

A mixture of compound 15-8 (crude, 0.72 g) and sodium acetate (0.55 g,6.7 mmol) in HMPA (5 mL) and DMF (5 mL) was heated at 100-105° C. for 24hours. The mixture was cooled to R.T., diluted with EA, washed with 5times, dried over sodium sulfate, and concentrated. The resulting crudewas dissolved in 7 N NH₃ in MeOH and stirred at R.T for 3 days. Thesolvent was evaporated, and the residue was chromatographed on silicagel with 5-12% MeOH in DCM to give5′-chloro-5′-deoxy-N²-(4-methoxytrityl)arabinosylguanosine (111 mg) andcompound 15-9 (102 mg).

Step 9. Compound (47)—

Compound 15-9 (42 mg) was dissolved in 80% aqueous formic acid, and theresulting solution stood at R.T. for 30 min. The solvent was evaporated,and the residue was co-evaporated with MeOH/toluene three times. Theresidue was the triturated with hot EA five times. The precipitate wasfiltered and washed with EA to give (47) (18.4 mg) as an ivory solid;NMR (DMSO-d₆) δ 10.6 (br, 1H), 7.713 (s, 1H), 6.49 (s, 2H), 6.17 (d,J=4.8 Hz, 1H), 5.95 (d, J=5.2 Hz, 1H), 5.84 (d, J=4.8 Hz, 1H), 5.50 (t,J=5.6 Hz, 1H), 4.32 (m, 2H), 3.68 (m, 2H); MS m/z=323.3 [M−1]⁻.

Example 48 Preparation of2-amino-9-(4-aido-2-deoxy-2-fluoro-1-ribofuranosyl)-6-methoxypurine (48)

Step 1. Compound 56-2—

To a stirred solution of 56-1 (2.7 g. 4.9 mmol) in pyridine (25 mL) wasadded Ac₂O (3.5 mL, 36 mmol) at 0° C. The mixture was stirred at R.T.overnight. The reaction was quenched with saturated NaHCO₃, extractedwith EA and washed with brine. The organic layer was dried over Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography (PE/EA=2:1 to 1:1) to afford 56-2 (2.6 g, yield 92.7%) asa white foam. ¹H NMR (CD₃OD, 400 MHz) δ 8.10 (s, 1H), 7.23-7.37 (m,13H), 6.85-6.89 (m, 2H), 5.98 (dd, J₁=5.2 Hz, J₂=13.2 Hz, 1H), 5.28 (dd,J₁=J₂=5.2 Hz, 1H), 5.11 (ddd, J₁=J₂=5.2 Hz, J₃=40.4 Hz, 1H), 4.52 (dd,J₁=J₂=1.2 Hz, 1H), 4.26 (d, J=2.4 Hz, 1H), 3.79 (s, 3H), 2.13 (s, 3H).

Step 2. Compound 56-3—

Compound 56-2 (2.6 g. 4.7 mmol), BOP (4.1 g, 9.4 mmol) and DBU (1.4 g,9.4 mmol) were dissolved in dry THF (50 mL). The mixture was stirred atR.T. for 1 hour. The solvent was evaporated under reduced pressure, andanhydrous MeOH (50 mL) and DBU (1.4 g, 9.4 mmol) was added. The mixturewas stirred at R.T. for 10 hours. The solvent was removed, and theresidue was re-dissolved in EA. The solution was washed with brine anddried over Na₂SO₄. The solvent was removed, and the residues waspurified by column chromatography (PE/EA=3:1 to 2:1) to afford compound56-3 as a white foam (1.5 g, 54.3%).

Step 3. Compound 56-4—

To a stirred solution of compound 56-3 (1.5 g, 2.6 mmol) in dry THF (50mL), 4-Methyl-morpholine (2.7 g, 26 mmol) and BnEt₃NN₃ (27 mL, 27 mmolin CH₃CN) was added a solution of I₂ (6.1 g, 24 mmol) in THF (100 mL)dropwise at 0° C. The mixture was stirred at R.T. for 18 hours. Thesolution was quenched with Na₂S₂O₃ solution and extracted with EA. Theorganic layer was washed with NaHCO₃ solution, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude products were purified bycolumn chromatography (PE/EA=4:1 to 2:1) to afford compound 56-4 as awhite foam (1.45 g, yield 76.7%).

Step 4. Compound 56-5—

To a stirred solution of compound 56-4 (1.4 g, 1.9 mmol) in dry pyridine(15 mL) was added BzCl (650 mg, 0.46 mmol). The mixture was stirred atR.T. for 2 hours. The solution was quenched with NaHCO₃ solution andextracted with EA. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(PE/EA=7:1 to 3:1) to afford compound 55-5 (1.3 g, yield 81.3%) as awhite solid.

Step 5. Compound 55-6—

To a stirred solution of compound 56-5 (1.2 g, 1.5 mmol) in dry DMF (50mL) were added NaOBz (1.5 g, 10.6 mmol) and 15-crown-5 (2.64 g, 17.6mmol). The mixture was stirred at 105° C. for 24 hours. The solution wasdiluted with water and extracted with EA. The organic layer was washedwith brine and dried over Na₂SO₄. The solvent was removed, and theresidue was purified by silica gel column chromatography (PE/EA=7:1 to3:1) to afford crude compound 56-6 (960 mg) as a white solid.

Step 6. Compound 56-7—

Compound 56-6 (950 mg) was dissolved in methanolic NH₃ (saturated). Themixture was stirred at R.T. for 12 hours. The solvent was removed, andthe residue was purified by silica gel column chromatography (PE/EA=3:1to 1:2) to afford to give compound 56-7 (350 mg, yield 48.8%) as whitesolids.

Step 7. Compound (48)—

Compound 56-7 (350 mg, 0.57 mmol) was dissolved in 80% formic acid (5mL). The mixture was stirred at R.T. for 30 mins. The solution wasco-evaporated with toluene for 5 times. The residue was purified byprep. TLC to give (48) (60 mg, 30.9%) as a white solid. ¹H NMR (MeOD,400 MHz) δ 8.05 (s, 1H), 6.43 (dd, J₁=2.8 Hz, J₂=17.2 Hz, 1H), 5.53(ddd, J₁=2.4 Hz, J₂=5.2 Hz, J₃=53.2 Hz, 1H), 4.94 (dd, J₁=5.2 Hz,J₂=18.8 Hz, 1H), 4.04 (s, 3H), 3.86 (d, J=12.4 Hz, 1H), 3.71 (d, J=12.4Hz, 1H); ESI-MS: m/z 341 [M+H]⁺.

Example 49 Preparation of2-amino-9-(4-aido-2-deoxy-2-fluoro-1-ribofuranosyl)-6-methoxypurine (49)

Step 1. Compound 57-2—

4′-Azido-2′-deoxy-2′-fluoroguanosine (57-1, 750 mg, 2 mmol) wassuspended in 50 ml of dry pyridine, acetic anhydride (1 ml, 10 mmol) andDMAP (122 mg. 1 mmol) were added. The reaction mixture was stirredovernight at 50° C. The solvent was evaporated, and the residuedissolved in the mixture of ethyl acetate and 10% NaHCO₃. The organicfraction were separated, washed with water, brine, dried over sodiumsulfate and evaporated. Compound 57-2 was isolated by columnchromatography in the linear gradient of methanol in DCM from 0 to 10%.

Step 2. Compound (49)—

Compound 57-2 (500 mg, 1 mmol) was dissolved in 10 mg of dry CHCl₃,TPSCl (1.5 mmol, 450 mg), triethylamine (2 mmol, 0.28 ml) and DMAP (0.1mmol, 13 mg) were added, and reaction mixture was left at R.T. for 20 h.When no starting material was detected, the solvent was evaporated andsodium ethylate was added (5 mmol, 340 mg). The reaction mixture wasleft overnight at R.T. LCMS analysis demonstrated a mixture ofmonoacetylated derivatives and (49). Additional sodium methylate wasadded (3 mmol, 200 mg), and mixture was heated for 4 h at 37° C. Thereaction mixture was neutralized with Dowex 50(H+). The Dowex wasfiltered, washed with ethanol and the combined liquid was evaporated.Purified was conducted by RP HPLC on Synergy 4 micron Hydro-RP column(Phenominex), and linear gradient of methanol from 15 to 75% in 50 mMtriethylammonium buffer was used for elution. The fractions containing(49) were evaporated, lyophilized 4 times with water to remove buffer,and purified again by column chromatography on silica gel in lineargradient of methanol in DCM from 0 to 10% to afford (49) (46 mg) as asolid; ¹H NMR (CD₃OD,): δ 8.03 (s, 1H), 6.42-6.40 (d, 1H), 5.60-5.45(dd, 1H), 4.96-4.95 (dd, 1H), 4.54-4.51 (m, 2H), 3.80-3.68 (m, 2H), 3.33(s, 1H), 1.43-1.40 (t, 3H); MS: 355.4 (M+H).

Example 50 Preparation of 4′-azido-1′-methylcytidine (50)

Step 1. Compound 37-1—

Compound 36-6 (2.5 g, 6.44 mmol) was dissolved in 80% TFA aqueoussolution (4 mL) at 0° C. The mixture was stirred at 0° C. for 8 min andthen was quenched by aqueous ammonia. The solution was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (0.8-1.5% MeOH in CH₂Cl₂) to give compound 37-1(1.8 g, 81%) as a colorless foam.

Step 2. Compound 37-2—

To a stirred solution of compound 37-1 (3.2 g, 9.20 mmol) in acetone (80mL) were added ammonium formate (6.5 g, 103 mmol) and 10% Pd/C (12.4 g).The mixture refluxed for 2 hours. The catalyst was filtered off andwashed with acetone. The combined filtrate was evaporated, and theresidue was purified by silica gel column chromatography (2-3.3% MeOH inCH₂Cl₂) to give compound 37-2 (2.1 g, 88%) as a white solid. ¹H NMR(DMSO-d6, 400 M Hz) δ 10.01 (s, 1H), 5.21 (d, J=4.8 Hz, 1H), 4.80 (t,J=5.2 Hz, 1H), 4.67 (d, J=6.8 Hz, 1H), 4.54 (t, J=4.8 Hz, 1H), 3.96-4.01(m, 1H), 3.87-3.93 (m, 1H), 3.77-3.817 (m, 1H), 3.57-3.62 (m, 1H),3.40-3.45 (m, 1H), 3.10-3.18 (m, 1H), 1.39 (s, 3H).

Step 3. Compound 37-3—

To a stirred suspension of compound 37-2 (1.40 g, 5.51 mmol), PPh₃ (4.33g, 16.53 mmol) and pyridine (3 mL) in anhydrous THF (30 mL) was added asolution of I₂ (2.80 g, 11.02 mmol) in THF (20 mL) dropwise at 0° C.After addition, the mixture was warmed to R.T. and stirred for 4 hours.The solution was quenched with sat. Na₂S₂O₃ aq. solution (10 mL) andextracted with EA (30 mL, 3 times). The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(DCM/MeOH=100:1 to 50:1) to afford compound 37-3 (1.40 g, 69.3%) as awhite solid.

Step 4. Compound 37-4—

Compound 37-3 (400 mg, 1.08 mmol) and CH₃ONa (176 mg, 3.26 mmol) weredissolved in anhydrous methanol (10 mL). The mixture was refluxed for 12hours. The reaction was quenched with dry-ice, and the solvent wasremoved. The residue was purified on a silica gel column.(MeOH:DCM=1:100 to 1:30) to afford compound 37-4 as a white solid (231mg, 88.8%). ¹H NMR (CD₃OD, 400 MHz) 7.62 (d, J=8.0 Hz, 1H), 5.67 (d,J=8.4 Hz, 1H), 4.59-4.84 (m, 2H), 4.42-4.45 (m, 1H), 4.33 (t, J=2 Hz,1H), 1.75 (s, 3H);

Step 5. Compound 37-5—

To a stirred solution of compound 37-4 (2.10 g, 8.75 mmol) and NMM (4.42g, 43.75 mmol) in anhydrous THF (20 mL) was added BnEt₃NN₃ (43.7 mL,43.8 mmol, 1 M in MeCN). The mixture was cooled to 0° C., and a solutionof I₂ (11.12 g, 43.75 mmol) in THF (20 mL) was added dropwise. Themixture was stirred at R.T. for 10 hours. N-acetyl cystein was addeduntil no gas evolved. Saturated Na₂S₂O₃ aq. solution was added until alight yellow solution achieved. The solution was concentrated and thendiluted with EA. The organic phase was washed with brine and dried overNa₂SO₄. The solvent was removed, and the residue was purified on asilica gel column (DCM:MeOH=50:1 to 30:1) to give compound 37-5 (2.43 g,68.1%) as a white solid.

Step 6. Compound 37-6—

To a stirred solution of compound 37-5 (0.46 g, 1.11 mmol) in anhydrouspyridine (8 mL) was added BzCl (0.31 mg, 2.78 mmol) dropwise at 0° C.The mixture was stirred at R.T. for 10 hours. The reaction was quenchedwith H₂O, and the solution was concentrated. The residue was dissolvedin EA and washed with saturated NaHCO₃. The organic layer was dried overNa₂SO₄ and concentrated. The residue was purified on a silica gel column(PE:EA=10:1 to 1:1) to give compound 37-6 (0.43 g, 62.9%) as a whitesolid.

Step 7. Compound 37-7—

Compound 37-6 (1.80 g, 2.91 mmol), BzONa (4.20 g, 29.10 mmol) and15-crown-5 (6.40 g, 29.10 mmol) were suspended in DMF (100 mL). Themixture was stirred at 90° C. for 1 day. The precipitate was removed byfiltration, and the filtrate was diluted with EA. The solution waswashed with brine and dried over Na₂SO₄. The solvent was removed, andthe residue was purified on a silica gel column (PE:EA=10:1 to 2:1) toafford compound 37-7 (1.52 g, 85.3%) as a white solid. ¹H NMR (CD₃OD,400 MHz) δ7.83-7.95 (m, 5H), 7.82 (d, J=1.2 Hz, 2H), 7.54-7.64 (m, 3H),7.40-7.47 (m, 5H), 7.31-7.35 (m, 2H), 6.60 (d, J=5.6 Hz, 1H), 6.10 (d,J=6.0 Hz, 1H), 5.53 (d, J=8.4 Hz, 1H), 4.59 (d, J=12 Hz, 1H), 1.98 (s,3H);

Step 8. Compound 37-8—

A solution of compound 37-7 (485 mg, 0.79 mmol), DMAP (193 mg, 1.58mmol) and TEA (160 mg, 1.58 mmol) in MeCN (5 mL) was treated with2,4,6-triispropylbenzenesulfonyl chloride (TPSCl, 479 mg, 1.58 mmol),and the mixture was stirred at room temperature for 12 hours. THF/NH₃(50 mL, saturated at 0° C.) was added. The mixture was stirred foradditional 2 hours. The solvent was evaporated under reduced pressure,and the residue was purified on a silica gel column (DCM/MeOH=100:1 to70:1) to give compound 37-8 (351 mg, 71.2%) as a white solid.

Step 9. Compound 37-9—

To a stirred solution of compound 37-8 (0.41 g, 0.66 mmol) in anhydrouspyridine (8 mL) was added BzCl (0.18 g, 1.32 mmol) dropwise at 0° C. Themixture was stirred at R.T. for 10 hours and then was quenched with H₂O.The solution was concentrated, and the residue was dissolved in EA andwashed with saturated NaHCO₃. The organic layer was dried over Na₂SO₄and concentrated. The residue was purified on a silica gel column(PE/EA=5/1 to 2/1) to give compound 37-9 (0.31 g, 76.7%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz) δ8.28 (d, J=8.0 Hz, 1H), 8.08 (d, J=7.6Hz, 2H), 7.75-7.98 (m, 6H), 7.59-7.63 (m, 2H), 7.41-7.53 (m, 6H),7.29-7.35 (m, 3H), 7.28 (s, 1H), 7.24 (s, 1H), 6.76-6.81 (m, 1H), 6.01(d, J=6.4 Hz, 1H), 4.81 (d, J=12.4 Hz, H), 4.59 (d, J=12.4 Hz, H), 2.15(s, 3H).

Step 10. Compound 50—

Compound 37-9 (0.41 g, 0.56 mmol) was dissolved in methanolic ammonia(30 mL, saturated), and the mixture was stirred at R.T. for 14 hours.The solvent was removed, and the residue was purified on a silica gelcolumn (DCM/MeOH=30:1 to 10:1) to give (50) as a white solid (40 mg,23.5%). ¹H NMR (CD₃OD, 400 MHz) δ8.13 (d, J=8.0 Hz, 1H), 5.84 (d, J=7.6Hz, 1H), 4.66 (d, J=5.2 Hz, 1H), 4.14 (d, J=5.2 Hz, 1H), 3.54 (dd, J₁=38Hz, J₂=12 Hz, 2H), 3.21 (s, 3H); ESI-MS: m/z=321.1 [M+Na]⁺, 619.1[2M+Na]⁺.

Example 51 Preparation of4′-azido-2′-deoxy-2′-α-fluoro-2′-β-methyluridine (51)

Compound 10-6 (0.22 g, 0.43 mmol) was dissolved in 100 mL methanolicammonia (saturated at 0° C.), and the mixture was stirred at R.T. for 12hours. The solvent was removed, and the residue was purified on a silicagel column (2-5% MeOH in DCM) to give (51) as a white solid (47 mg,36.4%). ¹H NMR (CD₃OD, 400 MHz) δ7.93 (d, J=8.4 Hz, 1H), 6.36 (s, 1H),5.71 (d, J=8.0 Hz, 1H), 4.17 (d, J=24.4 Hz, 1H), 3.78 (dd, J₁=46.4 Hz,J₂=12.0 Hz, 2H), 1.36 (d, J=22.4 Hz, 3H); ESI-MS: m/z 324.07 [M+Na]⁺.

Example 52 Preparation of 4′-azido-2′-deoxy-2′-fluorocytidine5′-(N,N-bis((S)-isopropoxycarbonyleth-1-yl))phosphorodiamidate (52)

To a stirred of suspension of phosphorous oxychloride (10.0 g, 65.7mmol) and L-aniline isopropyl ester (21.97 g, 131.5 mmol) in anhydrousDCM (400 mL) was added a solution of TEA (26.57 g, 263 mmol) in DCM (15mL) dropwise at −78° C. After addition, the mixture was warmed to R.T.and then stirred 6 hours. The solvent was removed, and the residue wasdissolved in methyl-butyl ether. The precipitate was removed byfiltration, and the filtrate was concentrated to give the crudecompound, which was purified on a silica gel column to give(N,N-bis((S)-isopropoxycarbonyleth-1-yl))phosphorodiamidic chloride (5.6g, yield: 27.35%) as a colorless oil. To a solution of compound (2) (90mg, 0.3 mmol) in anhydrous THF (5 mL) was added a solution of t-BuMgCl(0.50 mL, 1M in THF) dropwise at −78° C. The mixture was then stirred atR.T. for 30 min and re-cooled to −78° C. A solution of(N,N-bis((S)-isopropoxycarbonyleth-1-yl))phosphordiamidic chloride (0.50mL, 1M in THF) was added dropwise. After addition, the mixture wasstirred at R.T. for 14 hours. The reaction was quenched with HCOOH. Thesolvent was removed, and the residue was purified by prep. HPLC (0.1%HCOOH in MeCN and water) to give (52) (22.6 mg, 12.53%) as a whitesolid. ¹H NMR (CD₃OD, 400 MHz) δ 7.64 (d, J=7.6 Hz, 1H), 6.45 (br s,1H), 6.02 (d, J=7.6 Hz, 1H), 4.97-5.06 (m, 2H), 4.61 (t, J=12.0 Hz, 1H),4.34 (d, J=6.4 Hz, 2H), 3.86-3.97 (m, 2H), 1.35-1.41 (m, 6H), 1.24-1.27(m, 12H); ³¹P NMR (CD₃OD, 162 MHz) δ 13.81; ESI-LCMS: m/z=611 [M+H]⁺.

Example 53 Preparation of 4′-azido-2′-chloro-2′-deoxycytidine (53)

Step 1. Compound 42-1—

To a stirred suspension of compound 5-2 (1.1 g, 4.2 mmol) in anhydrousDMF (10 mL) was added AlCl₃ (1.4 g, 10.5 mmol) under N₂. The reactionstirred at 120° C. for 3 hours. The solution was concentrated, and theresidue was purified by silica gel column chromatography (1-20% MeOH inDCM) to give compound 42-1 (870 mg, 68.2%) as a white solid. ¹H NMR(CD₃OD, 400 M Hz) δ 7.92 (d, J=8.0 Hz, 1H), 6.39 (d, J=7.2 Hz, 1H), 5.76(d, J=8.0 Hz, 1H), 4.74 (dd, J₁=5.6, J₂=7.2 Hz, 1H), 4.44 (d, J=5.2 Hz,1H), 3.60 (dd, J₁=12.0 Hz, J₂=30.8 Hz, 2H).

Step 2. Compound 42-2—

To a stirred solution of compound 42-1 (870 mg, 2.9 mmol) in anhydrouspyridine (10 mL) was added TBSCl (1.3 g, 8.7 mmol) at R.T. The mixturewas stirred at R.T. for 14 hours. The precipitate was removed byfiltration, and filtrate was concentrated. The residue was purified on asilica gel column (10%-50% EA in PE) to give compound 42-2 (400 mg, 26%)as a white solid.

Step 3. Compound 42-3—

Compound 42-2 (400 mg, 0.7 mmol), DMAP (171 mg, 1.4 mmol), TPSCl (430mg, 14.4 mol) and Et₃N (141 mg, 1.4 mmol) were dissolved in MeCN (20mL). The mixture was stirred at R.T. for 14 hours. The reaction wasquenched with aqueous ammonia, and the mixture was stirred at R.T. for 2hours. The solvent was removed, and the residue was purified on a silicagel column (1-20% MeOH in DCM) to give compound 42-3 (175 mg, 47%) as awhite foam.

Step 4. Compound (53)—

A mixture of compound 42-3 (175 mg, 0.31 mmol) and NH₄F (100 mg, 2.7mmol) in MeOH (15 mL) was refluxed for 14 hours. The solvent wasremoved, and the residue was purified on a silica gel column (5%-10%MeOH in DCM) to give (53) (64.8 mg, 35.4%) as a white solid. ¹H NMR(CD₃OD, 400 M Hz): δ 7.91 (d, J=7.2 Hz, 1H), 6.40 (d, J=6.4 Hz, 1H),5.95 (d, J=7.2 Hz, 1H), 4.72 (dd, J₁=5.6 Hz, J₂=6.4 Hz, 1H), 4.47-4.48(m, 1H), 3.64 (dd, J₁=12.0 Hz, J₂=30.8 Hz, 2H); ESI-MS: m/z=303 [M+H]⁺.

Example 54 Preparation of 4′-azido-1′-methyluridine (54)

4′-Azido-1′-methyl-2′,3′,5′-O-tribenzoyluridine (37-7) (0.20 g, 0.34mmol) was dissolved in saturated methanolic ammonia (50 mL), and themixture was stirred at R.T. for 14 hours. The solvent was removed, andthe residue was purified on a silica gel column (DCM/MeOH=50:1 to 30:1)to give (54) as a white solid (47 mg, 46.0%). ¹H NMR (CD₃OD, 400 MHz)δ8.15 (d, J=8.4 Hz, 1H), 5.63 (d, J=8.4 Hz, 1H), 4.73 (d, J=5.6 Hz, 1H),4.17 (d, J=5.2 Hz, 1H), 3.67 (d, J=12.0 Hz, 1H), 3.55 (d, J=12.0 Hz,1H), 1.76 (s, 3H); ESI-negative-MS: m/z=298.1 [M−H]⁺, 597.2 [2M+H]⁺.

Example 55 Preparation of 4′-azidonucleoside 5′-triphosphates (61a-j)

1,2,4-Triazol (42 mg, 0.6 mmol) was suspended 1 ml of dry CH₃CN.Triethylamine was added (0.088 ml, 0.63 mmol), and the mixture wasvortexed to obtain a clear solution. After addition of POCl₃ (0.01 ml,0.1 mmol), the mixture was vortexed and left for 20 min, and thencentrifugated. The supernatant was added to the nucleoside (0.05 mmol),and the mixture was kept at ambient temperature for 1 hour.

Tris(tetrabutylammonium) hydrogen pyrophosphate (180 mg, 0.2 mmol) wasadded, and the mixture was kept for 2 hours more at R.T. The reactionwas quenched with water, and the 5′-triphosphate (61a-j) was isolated byIE chromatography on AKTA Explorer using column HiLoad 16/10 with QSepharose High Performance. The separation was done in a linear gradientof NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractionscontaining 5′-triphosphate were combined, concentrated and desalted byRP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lineargradient of methanol from 0 to 20% in 50 mM triethylammonium acetatebuffer (pH 7.5) was used for elution.

TABLE 1 The following compounds were synthesized according the procedureabove: ³¹P NMR ³¹P NMR ³¹P NMR MS Compound Pα Pβ Pδ (M⁻)

−12.33d −23.04 −9.95 525.3

−12.34d −23.15 −10.50d 543.1

−11.70 −20.64 −5.53 523.3

−12.31d −23.09 −9.58 524.4

−12.29d −22.97 −10.71 526.1

−12.40d −23.25t −10.92d 544.2

−12.13d −22.93 −10.49 565.3

−12.17d −22.20t −7.47d 583.1

−12.15d −22.51t −9.35 563.1

−12.26 −22.99 −10.75 549.2

Example 56 RSV Antiviral Assays

CPE reduction assays were performed as described by Sidwell and Huffmanet al., Appl Microbiol. (1971) 22(5):797-801 with slight modifications.HEp-2 cells (ATCC) at a concentration of 6000 cell/well were infectedwith RSV Long strain (ATCC) at a multiplicity of infection (m.o.i.) of0.01, and each of the test compounds were provided to duplicate wells atfinal concentrations starting from 100 μM using 1/3 stepwise dilutions.For each compound, two wells were set aside as uninfected, untreatedcell controls (CC), and two wells per test compound received virus onlyas a control for virus replication (VC). The assay was stopped after 6days, before all of the cells in the virus-infected untreated controlwells exhibited signs of virus cytopathology (giant cell formation,syncytia). At the end of the incubation, 20 μl of cell counting kit-8reagent (CCK-8, Dojindo Molecular Technologies, Inc.) were added to eachwell. After 4 hour incubation, the absorbance was measured in each wellaccording to manufacturer's instruction, and the 50% effectiveconcentration (EC₅₀) was calculated by using regression analysis, basedon the mean O.D. at each concentration of compound.

RT-PCR based assays were performed in HEp-2 cells (ATCC: CCL-23) at aconcentration of 20000 cell/well were plated in 96 well plates andincubated overnight. Each of the test compounds were 1/3 seriallydiluted and dosed to HEp-2 cells in duplicates. The highest finalconcentration for each compound was 100 uM. After 24 hour compoundpre-incubation, RSV A2 (ATCC: VR-1540) at MOI of 0.1 was added. Twowells per compound were set aside as uninfected, untreated cell controls(CC), and four wells per test compound received virus only as a controlfor virus replication (VC). The assay was stopped 4 days after virusinfection and conditioned media was removed for viral RNA isolation. Thequantities of the RSV virus were measured by real-time PCR using a setof RSV specific primers and probe. The data was analyzed with Prismsoftware with EC50 defined as drug concentration that reduced the viralload 50% from the viral control (VC).

Compounds of Formula (I) and Formula (II) are active in the assay asnoted in Tables 2 and 3, where ‘A’ indicates an EC₅₀<1 μM, ‘B’ indicatesan EC₅₀ of ≧1 μM and <10 μM, ‘C’ indicates an EC₅₀≧10 μM and <100 μM,and ‘D’ indicates an EC₅₀≧100 μM.

TABLE 2 Activity of compounds as determined by CPE assay No. EC₅₀ 1 A 2A 3 — 4 — 5 D 6 D 7 C 8 D 9 D 10 A 11 A 12 D 13 — 14 — 15 A 16 — 17 D 18B 19 D 20 D 21 A 22 A 23 B 24 D 25 D 26 D 27 A 28 D 29 A 30 — 31 A 32 D33 A 34 D 35 A 36 D 37 B 38 D 39 D 40 D 41 D 42 C 43 C 44 D 45 D 46 D 47D 48 B 49 D 50 D 51 D 52 — 53 — 54 — — — — — — — — — — — — —

TABLE 3 Activity of compounds as determined by RT-PCR assay No. EC₅₀ 1 A2 A 3 — 4 — 5 D 6 — 7 B 8 — 9 — 10 A 11 A 12 D 13 — 14 — 15 A 16 — 17 D18 B 19 D 20 D 21 A 22 A 23 B 24 D 25 D 26 D 27 A 28 D 29 A 30 D 31 A 32— 33 A 34 D 35 A 36 D 37 B 38 D 39 D 40 D 41 D 42 D 43 C 44 D 45 D 46 D47 D 48 A 49 D 50 D 51 D 52 — 53 B 54 — — — — — — — — — — — — —

Example 57 Influenza Antiviral Assay

To test representative compounds of the invention for their potenciesagainst Influenza A/WSN/33 virus (ATCC: VR-1520), A549 cells (ATCC:CCL-185, human lung carcinoma) were plated at 5000 cells per well in 100μs of Ham's F12 medium supplemented with ten percent fetal bovine serum(FBS) and one percent penicillin and streptomycin (Pen/Strep) in a 96well plate. Twenty-four hours post plating, medium was discarded and thecells were washed one time with phosphate buffered saline (PBS) andreplaced with Ham's F12 medium with 0.3 percent FBS and one percentPen/Strep. Each of the test compounds was three fold serially dilutedand dosed to A549 cells in duplicates. The highest final concentrationfor each compound was 100 μM. After 24 hour compound pre-incubation,Influenza A/WSN/33 virus was added at MOI of 0.01 and incubated for 72hours. Two wells per compound were set aside as uninfected, untreatedcell controls, and four wells per compound received virus only as acontrol for virus replication (VC). The quantities of the Influenzavirus in each well were measured by real-time PCR using a set ofInfluenza A/WSN/33 strain specific primers and probe. The data wasanalyzed with Microsoft Excel software with percent inhibition definedas compared to the vehicle control. As shown in Table 4, compounds ofFormula (I) and Formula (II) are active in the assay.

TABLE 4 Activity of representative compounds as determined by RT-PCRassay. No. Compound Concentration Percent Inhibition  2 30 μM 99.8% 1030 μM 83.3% 27 30 μM   91% 28 30 μM 94.6% 30 30 μM 99.9% 50 30 μM 90.9%

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it will be understood by those of skill in the art thatnumerous and various modifications can be made without departing fromthe spirit of the present disclosure. Therefore, it should be clearlyunderstood that the forms disclosed herein are illustrative only and arenot intended to limit the scope of the present disclosure, but rather toalso cover all modification and alternatives coming with the true scopeand spirit of the invention.

What is claimed is:
 1. A method of ameliorating or treating a viralinfection selected from a paramyxovirus viral infection and anorthomyxovirus viral infection comprising administering atherapeutically effective amount of a compound of Formula (II), or apharmaceutically acceptable salt thereof, to a subject suffering fromthe viral infection, wherein the compound of Formula (II) has thestructure:

wherein: B^(1a) is selected from the group consisting of an optionallysubstituted heterocyclic base and an optionally substituted heterocyclicbase with a protected amino group; R^(1a) is selected from the groupconsisting of hydrogen, an optionally substituted acyl,

n^(a) is 0, 1, or 2; R^(2a) and R^(1a) are independently selected fromthe group consisting of hydrogen, an optionally substituted C₁₋₆ alkyland an optionally substituted C₁₋₆ haloalkyl; R^(4a) is selected fromthe group consisting of hydrogen, halogen, an optionally substitutedC₁₋₆ alkyl, —OR^(18a) and —OC(═O)R^(19a); R^(5a) is selected from thegroup consisting of hydrogen, halogen, an optionally substituted C₁₋₆alkyl, —OR^(20a) and —OC(═O)R^(21a); R^(6a) is selected from the groupconsisting of hydrogen, halogen, an optionally substituted C₁₋₆ alkyl,—OR^(22a) and —OC(═O)R^(23a); or R^(5a) and R^(6a) are both oxygen atomsand linked together by a carbonyl group; R^(7a) is selected from thegroup consisting of hydrogen, halogen, optionally substituted C₁₋₆alkyl, —OR^(24a) and —OC(═O)R^(25a); R^(8a) is selected from the groupconsisting of hydrogen, an optionally substituted C₁₋₆ alkyl and anoptionally substituted C₁₋₆ haloalkyl; R^(9a) and R^(12a) areindependently absent or hydrogen; R^(10a) is absent or hydrogen; eachR^(11a) is independently absent or hydrogen; R^(13a) is absent orhydrogen; R^(14a) is selected from the group consisting of an —O—optionally substituted aryl, an —O— optionally substituted heteroaryland an —O— optionally substituted heterocyclyl, and R^(15a) is anoptionally substituted N-linked amino acid or an optionally substitutedN-linked amino acid ester derivative; or R^(14a) is an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative, and R^(15a) is an optionally substitutedN-linked amino acid or an optionally substituted N-linked amino acidester derivative; or R^(14a) is O⁻, hydroxy or an —O— optionallysubstituted C₁₋₆ alkyl, and R^(15a) and R^(5a) together are O; R^(16a)is selected from the group consisting of an —O— optionally substitutedaryl, an —O— optionally substituted heteroaryl and an —O— optionallysubstituted heterocyclyl, and R^(17a) is an optionally substitutedN-linked amino acid or an optionally substituted N-linked amino acidester derivative; or R^(16a) is an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivative,and R^(17a) is an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative; or R^(16a)is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl, and R^(17a)and R^(5a) together are O; R^(18a), R^(20a), R^(22a) and R²⁴ areindependently hydrogen or an optionally substituted C₁₋₆ alkyl; andR^(19a), R^(21a), R^(23a) and R^(25a) are independently selected fromthe group consisting of an optionally substituted C₁₋₆ alkyl and anoptionally substituted C₃₋₆ cycloalkyl.
 2. The method of claim 1,wherein R^(2a) and R^(3a) are hydrogen.
 3. The method of claim 1,wherein at least one of R^(2a) and R^(3a) is hydrogen; and the other ofR^(2a) and R^(3a) is an optionally substituted C₁₋₆ alkyl or anoptionally substituted C₁₋₆ haloalkyl.
 4. The method of claim 1, whereinR^(1a) is hydrogen or an optionally substituted acyl.
 5. The method ofclaim 1, wherein R^(1a) is selected from the group consisting of


6. The method of claim 5, wherein R^(1a) is

and R^(14a) is an optionally substituted aryl, an optionally substitutedN-linked α-amino acid or an optionally substituted N-linked α-amino acidester derivative.
 7. The method of claim 6, wherein R^(15a) is anoptionally substituted N-linked α-amino acid or an optionallysubstituted N-linked α-amino acid ester derivative.
 8. The method ofclaim 5, wherein R^(1a) is

and R^(14a) and R^(15a) each independently have the structure:

wherein R^(26a) is hydrogen or an optionally substituted C₁₋₄-alkyl;R^(27a) is selected from the group consisting of hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₆aryl, an optionally substituted C₁₀ aryl, and an optionally substitutedaryl(C₁₋₆ alkyl); and R^(28a) is selected from the group consisting ofhydrogen, an optionally substituted C₁₋₆-alkyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₆ alkyl), and an optionally substitutedhaloalkyl, or R^(26a) and R^(27a) are taken together to form anoptionally substituted C₃₋₆ cycloalkyl.
 9. The method of claim 8,wherein R^(26a) is hydrogen; R^(27a) is hydrogen or methyl; and R^(28a)is methyl or benzyl.
 10. The method of claim 5, wherein R^(1a) is

and R^(14a) is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl,and R^(15a) and R^(5a) together are O.
 11. The method of claim 5,wherein R^(1a) is

and R^(16a) is an —O— optionally substituted aryl, an optionallysubstituted N-linked α-amino acid or an optionally substituted N-linkedα-amino acid ester derivative.
 12. The method of claim 11, whereinR^(17a) is an optionally substituted N-linked α-amino acid or anoptionally substituted N-linked α-amino acid ester derivative.
 13. Themethod of claim 5, wherein R^(1a) is

and R^(16a) and R^(17a) each independently have the structure:

wherein: R^(29a) is selected from the group consisting of hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); R^(30a) is hydrogen or anoptionally substituted C₁₋₄-alkyl; and R^(31a) is selected from thegroup consisting of hydrogen, an optionally substituted C₁₋₆-alkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted aryl,an optionally substituted aryl(C₁₋₆ alkyl) and an optionally substitutedC₁₋₆ haloalkyl, or R^(29a) and R^(30a) are taken together to form anoptionally substituted C₃₋₆ cycloalkyl.
 14. The method of claim 13,wherein R^(29a) is hydrogen; R^(30a) is hydrogen or methyl; and R^(31a)is methyl or benzyl.
 15. The method of claim 1, wherein R^(1a) is

and R^(16a) is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl;and R^(17a) and R^(5a) together are O.
 16. The method of claim 1,wherein B^(1a) is selected from the group consisting of:

wherein: R^(A2a) is selected from the group consisting of hydrogen,halogen and NHR^(J2a), wherein R^(J2a) is selected from the groupconsisting of hydrogen, —C(═O)R^(K2a) and —C(═O)OR^(L2a); R^(B2a) ishalogen or NHR^(W2a), wherein R^(W2a) is selected from the groupconsisting of hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₃₋₈cycloalkyl, —C(═O)R^(M2a) and —C(═O)OR^(N2a); R^(C2a) is hydrogen orNHR^(O2a), wherein R^(O2a) is selected from the group consisting ofhydrogen, —C(═O)R^(P2a) and —C(═O)OR^(Q2a); R^(D2a) is selected from thegroup consisting of hydrogen, halogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₂₋₆ alkenyl and an optionallysubstituted C₂₋₆ alkynyl; R^(E2a) is selected from the group consistingof hydrogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₃₋₈ cycloalkyl, —C(═O)R^(R2a) and —C(═O)OR^(S2a); R^(F2a)is selected from the group consisting of hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; Y^(2a) is N orCR^(I2a), wherein R^(I2a) is selected from the group consisting ofhydrogen, halogen, an optionally substituted C₁₋₆-alkyl, an optionallysubstituted C₂₋₆-alkenyl and an optionally substituted C₂₋₆-alkynyl;R^(G2a) is an optionally substituted C₁₋₆ alkyl; R^(H2a) is hydrogen orNHR^(T2a), wherein R^(T2a) is independently selected from the groupconsisting of hydrogen, —C(═O)R^(U2a) and —C(═O)OR^(V2a), R^(Y2a) ishydrogen or NHR^(Z2a), wherein R^(Z2a) is selected from the groupconsisting of hydrogen, —C(═O)R^(AA2a) and —C(═O)OR^(BB2a); R^(K2a),R^(L2a), R^(M2a), R^(N2a), R^(P2a), R^(Q2a), R^(R2a), R^(S2a), R^(U2a),R^(V2a), R^(AA2a) and R^(BB2a) are independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkenyl, C₃₋₆ cycloalkynyl, C₆₋₁₀ aryl, heteroaryl,heteroalicyclyl, aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) andheteroalicyclyl(C₁₋₆ alkyl).
 17. The method of claim 16, wherein B^(1a)is selected from the group consisting of


18. The method of claim 1, wherein R^(7a) is —OR^(24a) or an optionallysubstituted C₁₋₆ alkyl; and R^(8a) is hydrogen.
 19. The method of claim1 wherein R^(7a) is hydrogen or a halogen; and R^(8a) is hydrogen. 20.The method of claim 1, wherein R^(5a) is —OR^(20a).
 21. The method ofclaim 1, wherein R^(6a) is —OR^(22a), hydrogen or a halogen.
 22. Themethod of claim 1, wherein R^(5a) and R^(6a) are both oxygen atoms andlinked together by a carbonyl group.
 23. The method of claim 1, whereinthe compound is selected from the group consisting of:


24. The method of claim 1, wherein the compound is selected from thegroup consisting of:


25. The method of claim 1, wherein the paramyxovirus viral infection isa human respiratory syncytial virus infection.
 26. The method of claim1, wherein the orthomyxovirus viral infection is an influenza virusinfection (influenza A, B and/or C).
 27. A method of inhibitingreplication of a virus selected from paramyxovirus and orthomyxoviruscomprising contacting a cell infected with the virus with an effectiveamount of a compound selected from a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a compound of Formula(II), or a pharmaceutically acceptable salt thereof.
 28. A method ofameliorating or treating a viral infection selected from paramyxovirusviral infection and orthomyxovirus viral infection comprising contactinga cell infected with the virus with an effective amount of a compoundselected from a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a compound of Formula (II), or apharmaceutically acceptable salt thereof.
 29. A method of amelioratingor treating a viral infection selected from a paramyxovirus viralinfection and an orthomyxovirus viral infection comprising administeringa therapeutically effective amount of a compound selected from acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a compound of Formula (II), or a pharmaceutically acceptable saltthereof, in combination with one or more agents to a subject sufferingfrom the viral infection.
 30. The method of claim 29, wherein theparamyxovirus viral infection is a human respiratory syncytial virusinfection; and wherein the one or more agents is selected from the groupconsisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, BMS-433771,RFI-641, RSV604, MDT-637, BTA9881, TMC-353121, MBX-300 and YM-53403. 31.A method of treating or ameliorating a viral infection selected from aparamyxovirus viral infection and an orthomyxovirus viral infectioncomprising contacting a cell infected with the virus with an effectiveamount of a compound selected from a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a compound of Formula(II), or a pharmaceutically acceptable salt thereof, in combination withone or more agents.
 32. The method of claim 31, wherein theorthomyxovirus viral infection is an influenza virus infection; andwherein the one or more agents is selected from the group consisting ofamantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir,favipirvir, fludase, ADS-8902, IFN-b and beraprost.
 33. A compound ofFormula (I) or a pharmaceutically acceptable salt thereof:

wherein: B¹ is selected from the group consisting of an optionallysubstituted heterocyclic base and an optionally substituted heterocyclicbase with a protected amino group; R¹ is selected from the groupconsisting of hydrogen, an optionally substituted acyl,

n is 0, 1 or 2; R² and R³ are independently selected from the groupconsisting of hydrogen, an optionally substituted C₁₋₆ alkyl and anoptionally substituted C₁₋₆ haloalkyl; R⁴ is selected from the groupconsisting of hydrogen, halogen, optionally substituted C₁₋₆ alkyl,—OR¹⁸ and —OC(═O)R¹⁹; R⁵ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁₋₆ alkyl, —OR²⁰ and—OC(═O)R²¹; R⁶ is selected from the group consisting of hydrogen,halogen, optionally substituted C₁₋₆ alkyl, —OR²² and —OC(═O)R²³; or R⁵and R⁶ are both oxygen atoms and linked together by a carbonyl group; R⁷is selected from the group consisting of hydrogen, halogen, optionallysubstituted C₁₋₆ alkyl, —OR²⁴ and —OC(═O)R²⁵; R⁸ is selected from thegroup consisting of hydrogen, an optionally substituted C₁₋₆ alkyl andan optionally substituted C₁₋₆ haloalkyl; R⁹, R¹⁰, each R¹¹, R¹² and R¹³are independently absent or hydrogen; R¹⁴ is selected from the groupconsisting of an —O— optionally substituted aryl, an —O— optionallysubstituted heteroaryl and an —O— optionally substituted heterocyclyl,and R¹⁵ is

 or R¹⁴ is an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative, and R¹⁵ isan optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative; or R¹⁴ is O⁻, hydroxyor an —O— optionally substituted C₁₋₆ alkyl, and R¹⁵ and R⁵ together areO; R¹⁶ is selected from the group consisting of an —O— optionallysubstituted aryl, an —O— optionally substituted heteroaryl and an —O—optionally substituted heterocyclyl, and R¹⁷ is an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative; or R¹⁶ is an optionally substitutedN-linked amino acid or an optionally substituted N-linked amino acidester derivative, and R¹⁷ is an optionally substituted N-linked aminoacid or an optionally substituted N-linked amino acid ester derivative;or R¹⁶ is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl, andR¹⁷ and R⁵ together are O; R¹⁸, R²⁰, R²² and R²⁴ are independentlyselected from the group consisting of hydrogen and an optionallysubstituted C₁₋₆ alkyl; R¹⁹, R²¹, R²³ and R²⁵ are independently selectedfrom the group consisting of an optionally substituted C₁₋₆ alkyl and anoptionally substituted C₃₋₆ cycloalkyl; R²⁶ is hydrogen or an optionallysubstituted C₁₋₄-alkyl; R²⁷ is selected from the group consisting ofhydrogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₁₋₆ haloalkyl, an optionally substituted C₃₋₆ cycloalkyl,an optionally substituted C₆ aryl, an optionally substituted C₁₀ aryland an optionally substituted aryl(C₁₋₆ alkyl); and R²⁸ is selected fromthe group consisting of hydrogen, an optionally substituted C₁₋₆-alkyl,an optionally substituted C₃₋₆ cycloalkyl, an optionally substitutedaryl, an optionally substituted aryl(C₁₋₆ alkyl) and an optionallysubstituted haloalkyl, or R²⁶ and R²⁷ are taken together to form anoptionally substituted C₃₋₆ cycloalkyl; provided that when R², R³, R⁴,and R⁸ are all hydrogen, R¹ cannot be hydrogen; provided that when R²and R³ are both hydrogen, R⁵ is hydroxy, R⁴ and R⁶ are both hydrogen, R⁷is halogen, R⁸ is hydrogen, and B¹ is

 then R¹ cannot be

 wherein n is 0 or 2; and R⁹, R¹⁰ and R¹¹ are hydrogen; provided thatwhen R¹ is

 R² and R³ are both hydrogen, R⁴ is hydrogen, R⁵ is OH, R⁶ is selectedfrom the group consisting of halogen, hydrogen, and hydroxy, R⁷ isselected from the group consisting of halogen, hydrogen, methyl, andhydroxy, R⁸ is hydrogen, B¹ selected from the group consisting of

 R¹⁴ is an —O— optionally substituted aryl, then R¹⁵ cannot be

 wherein R²⁶ is hydrogen or an optionally substituted C₁₋₄ alkyl; R²⁷ isselected from the group consisting of hydrogen, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CH₂SCH₃, —CH₂CH₂COOCH₂CH₃,—CH₂C(═O)OCH₂CH₃, —CH₂-indol-3-yl, —CH₂phenyl, unsubstituted cyclopentyland —CH(CH₂CH₃)CH₃; and R²⁸ is selected from the group consisting ofunsubstituted C₁₋₄-alkyl, unsubstituted benzyl and CH₂CF₃; provided thatwhen R¹ is

 R², R³, R⁴, R⁷ and R⁸ are all hydrogen, R⁵ is hydroxy, R⁶ is hydroxy,R¹⁴ is —O-naphthyl, R¹⁵ is

 wherein R²⁶ is hydrogen, R²⁷ is methyl and R²⁸ is benzyl, then B¹cannot be

provided that when R¹ is

 R², R³, R⁴, R⁷ and R⁸ are all hydrogen, R⁵ is hydroxy, R⁶ is hydroxy,R¹⁴ is —O-phenyl, R¹⁵ is

 wherein R²⁶ and R²⁷ are taken together to form an substitutedcyclopentyl ring and R²⁸ is an unsubstituted C₁₋₄ alkyl or benzyl, thenB¹ cannot be

provided that B¹ cannot be adenine or an optionally substituted adeninewhen at least one of R² and R³ is not hydrogen; and provided that acompound of Formula (I) cannot have the following structure:


34. The compound of claim 33, wherein R² and R³ are hydrogen; or whereinat least one of R² and R³ is hydrogen; and the other of R² and R³ is anoptionally substituted C₁₋₆ alkyl or an optionally substituted C₁₋₆haloalkyl.
 35. The compound of claim 33, wherein R¹ is selected from thegroup consisting of hydrogen, an optionally substituted acyl,


36. The compound of claim 33, wherein R¹ is

and R¹⁴ is an —O— optionally substituted aryl; and R²⁶ is hydrogen; R²⁷is hydrogen or methyl; and R²⁸ is methyl or benzyl; or R¹ is

R¹⁴ is an optionally substituted N-linked α-amino acid or an optionallysubstituted N-linked α-amino acid ester derivative; and R¹⁵ is anoptionally substituted N-linked α-amino acid or an optionallysubstituted N-linked α-amino acid ester derivative; or R¹ is

R¹⁴ is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl, and R¹⁵and R⁵ together are O.
 37. The compound of claim 33, wherein R¹ is

R¹⁶ is an —O— optionally substituted aryl; and R¹⁷ is an optionallysubstituted N-linked α-amino acid or an optionally substituted N-linkedα-amino acid ester derivative; or R¹ is

R¹⁶ is an optionally substituted N-linked α-amino acid or an optionallysubstituted N-linked α-amino acid ester derivative; and R¹⁷ is anoptionally substituted N-linked α-amino acid or an optionallysubstituted N-linked α-amino acid ester derivative; or R¹ is

R¹⁶ is O⁻, hydroxy or an —O— optionally substituted C₁₋₆ alkyl; and R¹⁷and R⁵ together are O.
 38. The compound of claim 33, wherein R¹ is

and R¹⁶ and R¹⁷ each independently have the structure:

wherein: R²⁹ is selected from the group consisting of hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); R³⁰ is hydrogen or anoptionally substituted C₁₋₄-alkyl; and R³¹ is selected from the groupconsisting of hydrogen, an optionally substituted C₁₋₆-alkyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted aryl,an optionally substituted aryl(C₁₋₆ alkyl) and an optionally substitutedC₁₋₆ haloalkyl, or R²⁹ and R³⁰ are taken together to form an optionallysubstituted C₃₋₆ cycloalkyl.
 39. The compound of claim 33, wherein B¹ isselected from the group consisting of:

wherein: R^(A2) is selected from the group consisting of hydrogen,halogen and NHR^(J2), wherein R^(J2) is selected from the groupconsisting of hydrogen, —C(═O)R^(K2) and —C(═O)OR^(L2); R^(B2) ishalogen or NHR^(W2), wherein R^(W2) is selected from the groupconsisting of hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₃₋₈cycloalkyl, —C(═O)R^(M2) and —C(═O)OR^(N2); R^(C2) is hydrogen orNHR^(O2), wherein R^(O2) is selected from the group consisting ofhydrogen, —C(═O)R^(P2) and —C(═O)OR^(Q2); R^(D2) is selected from thegroup consisting of hydrogen, halogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₂₋₆ alkenyl and an optionallysubstituted C₂₋₆ alkynyl; R^(E2) is selected from the group consistingof hydrogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₃₋₈ cycloalkyl, —C(═O)R^(R2) and —C(═O)OR^(S2); R^(F2) isselected from the group consisting of hydrogen, halogen, an optionallysubstituted C₁₋₆alkyl, an optionally substituted C₂₋₆ alkenyl and anoptionally substituted C₂₋₆ alkynyl; Y² is N or CR^(I2), wherein R^(I2)is selected from the group consisting of hydrogen, halogen, anoptionally substituted C₁₋₆-alkyl, an optionally substitutedC₂₋₆-alkenyl and an optionally substituted C₂₋₆-alkynyl; R^(G2) is anoptionally substituted C₁₋₆ alkyl; R^(H2) is hydrogen or NHR^(T2),wherein R^(T2) is independently selected from the group consisting ofhydrogen, —C(═O)R^(U2) and —C(═O)OR^(V2), R^(Y2) is hydrogen orNHR^(Z2), wherein R is selected from the group consisting of hydrogen,—C(═O)R^(AA2) and —C(═O)OR^(BB2); R^(K2), R^(L2), R^(M2), R^(N2),R^(P2), R^(Q2), R^(R2), R^(S2), R^(U2), R^(V2), R^(AA2) and R^(BB2) areindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₆cycloalkynyl, C₆₋₁₀ aryl, heteroaryl, heteroalicyclyl, aryl(C₁₋₆ alkyl),heteroaryl(C₁₋₆ alkyl) and heteroalicyclyl(C₁₋₆ alkyl).
 40. The compoundof claim 39, wherein B¹ is selected from the group consisting of


41. The compound of claim 33, wherein R⁷ is —OR²⁴ or an optionallysubstituted C₁₋₆ alkyl; and R⁸ is hydrogen.
 42. The compound of claim33, wherein R⁷ is hydrogen or a halogen; and R⁸ is hydrogen.
 43. Thecompound of claim 33, wherein R⁵ is —OR²⁰.
 44. The compound of claim 33,wherein R⁶ is —OR²², hydrogen or a halogen.
 45. The compound of claim33, wherein R⁵ and R⁶ are both oxygen atoms and linked together by acarbonyl group.
 46. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 33, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, excipient, or combination thereof.